Collagen: Difference between revisions

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== Types ==
== Types ==
There are over 28 types of collagen found in the human body.<ref name=":3">{{Cite journal|last=Wu|first=Marlyn|last2=Crane|first2=Jonathan S.|date=2019|title=Biochemistry, Collagen Synthesis|url=http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29939531}}</ref> Over 90% is made of of these fives types<ref name=":3" />:
There are over 28 types of collagen found in the human body.<ref name="Wu2019">{{Cite book | last = Wu | first = Marlyn | last2 = Crane | first2 = Jonathan S. | date = 2019 | title=Biochemistry, Collagen Synthesis |url =http://www.ncbi.nlm.nih.gov/books/NBK507709/|location=Treasure Island (FL)| publisher = StatPearls Publishing|pmid=29939531}}</ref> Over 90% is made of of these fives types<ref name="Wu2019" />:
* Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
* Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
* Type II: cartilage (main collagenous component of cartilage)
* Type II: cartilage (main collagenous component of cartilage)
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* Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
* Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
* Type V: cell surfaces, hair, and placenta
* Type V: cell surfaces, hair, and placenta
The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament.<ref>{{Cite web|url=https://www.orthobullets.com/basic-science/9016/ligaments|title=|last=|first=|authorlink=|last2=|first2=|authorlink2=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref> Elastin is also found at 4–9% of the dry weight in ligaments.<ref>{{Cite journal|last=Zitnay|first=Jared L.|last2=Weiss|first2=Jeffrey A.|date=Dec 2018|title=Load Transfer, Damage and Failure in Ligaments and Tendons|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454883/|journal=Journal of orthopaedic research : official publication of the Orthopaedic Research Society|volume=36|issue=12|pages=3093–3104|doi=10.1002/jor.24134|issn=0736-0266|pmc=6454883|pmid=30175857}}</ref>
The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament.<ref>{{Cite web | url = https://www.orthobullets.com/basic-science/9016/ligaments | title = Ligaments | last = | first = | authorlink = | date = | website = orthobullets.com|access-date=2019-09-16}}</ref> Elastin is also found at 4–9% of the dry weight in ligaments.<ref>{{Cite journal | last = Zitnay | first = Jared L. | last2 = Weiss | first2 = Jeffrey A. | date = Dec 2018 | title = Load Transfer, Damage and Failure in Ligaments and Tendons |url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454883/ | journal = Journal of orthopaedic research : official publication of the Orthopaedic Research Society|volume=36 | issue = 12 | pages = 3093–3104|doi=10.1002/jor.24134|issn=0736-0266|pmc=6454883|pmid=30175857}}</ref>


== Biology ==
== Biology ==


=== Components ===
=== Components ===
Collagen is made up primarily of the amino acids [[glycine]] and [[proline]]. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline.<ref>{{Cite journal|last=Szulc|first=Pawel|date=Oct 2018|title=Bone turnover: Biology and assessment tools|url=https://www.ncbi.nlm.nih.gov/pubmed/30449551|journal=Best Practice & Research. Clinical Endocrinology & Metabolism|volume=32|issue=5|pages=725–738|doi=10.1016/j.beem.2018.05.003|issn=1878-1594|pmid=30449551|last2=|first2=|pmc=|quote=|last3=|first3=|last4=|first4=|last5=|first5=|last6=|first6=|last7=|first7=|last8=|first8=|author-link=|author-link2=|access-date=|author-link3=|author-link4=|author-link5=|author-link6=|via=}}</ref> X can be any of the other 17 amino acids. Every third amino acid is glycine.<ref name=":3" />  
Collagen is made up primarily of the amino acids glycine and proline. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline.<ref>{{Cite journal | last = Szulc | first = Pawel | date = Oct 2018 | title = Bone turnover: Biology and assessment tools |url =https://www.ncbi.nlm.nih.gov/pubmed/30449551 | journal = Best Practice & Research. Clinical Endocrinology & Metabolism|volume=32 | issue = 5 | pages = 725–738|doi=10.1016/j.beem.2018.05.003|issn=1878-1594|pmid=30449551 | last2 = | first2 = |pmc=|quote=|access-date=|via=}}</ref> X can be any of the other 17 amino acids. Every third amino acid is glycine.<ref name="Wu2019" />  


=== Co-factors ===
=== Co-factors ===
[[Vitamin C]] is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a [[mast cell]] stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and [[scurvy]].{{Citation needed|reason=}}
[[Vitamin C]] is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a [[mast cell]] stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and [[scurvy]].<ref name="vitC-deficiency">https://www.statpearls.com/ArticleLibrary/viewarticle/28798</ref>


=== Structure ===
=== Structure ===
Collagen is composed of three chains that wind together to form a triple helix.<ref name=":3" />  
Collagen is composed of three chains that wind together to form a triple helix.<ref name="Wu2019" />  


=== Biosynthesis ===
=== Biosynthesis ===
Collagen synthesis occurs mainly in [[Fibroblast|fibroblasts]], cells whose many function is the synthesis of collagen and [[stroma]].<ref name=":3" /> Synthesis occurs in both intracellular and extracellular spaces.<ref name=":3" />  
Collagen synthesis occurs mainly in [[Fibroblast|fibroblasts]], cells whose many function is the synthesis of collagen and stroma.<ref name="Wu2019" /> Synthesis occurs in both intracellular and extracellular spaces.<ref name="Wu2019" />  


== Collagen-degrading factors ==
== Collagen-degrading factors ==


=== Pathogens ===
=== Pathogens ===
Infection can degrade collagen via direct secretion<ref name=":1">{{Cite journal|last=Harrington|first=D J|date=Jun 1996|title=Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease.|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC174012/|journal=Infection and Immunity|volume=64|issue=6|pages=1885–1891|issn=0019-9567|pmid=8675283}}</ref> of collagenases and other [[Enzyme|enzymes]] (in the case of [[bacteria]]) or increased host production of [[Matrix metalloproteinase|matrix metalloproteinases]] (MMPs) as part of the normal [[immune response]] (in the case of bacteria and [[Virus|viruses]]). Numerous bacteria secrete their own [[collagenase|collagenases]].<ref name=":1" /><ref>{{Cite journal|last=Duarte|first=Ana Sofia|last2=Correia|first2=Antonio|last3=Esteves|first3=Ana Cristina|date=2016|title=Bacterial collagenases - A review|url=https://www.ncbi.nlm.nih.gov/pubmed/24754251|journal=Critical Reviews in Microbiology|volume=42|issue=1|pages=106–126|doi=10.3109/1040841X.2014.904270|issn=1549-7828|pmid=24754251}}</ref> [[Borrelia]] spirochetes upregulate production of human collagenase (MMP-1) and [[gelatinase B]] (MMP-9)<ref>{{Cite journal|last=Gebbia|first=Joseph A.|last2=Coleman|first2=James L.|last3=Benach|first3=Jorge L.|date=2001-01-01|title=Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells|url=https://iai.asm.org/content/69/1/456|journal=Infection and Immunity|language=en|volume=69|issue=1|pages=456–462|doi=10.1128/IAI.69.1.456-462.2001|issn=0019-9567|pmid=11119537}}</ref>, an enzyme that can degrade both [[elastin]] and collagen.<ref>{{Cite web|url=https://www.sciencedirect.com/topics/neuroscience/gelatinase-b|title=ScienceDirect|website=www.sciencedirect.com|access-date=2018-11-09}}</ref> MMP-8 and MMP-9 are upregulated in bacterial [[meningitis]] and the latter is associated with an increased risk of [[blood-brain barrier]] breakdown and neurological sequale such as [[epilepsy]] and [[Cognitive dysfunction|cognitive impairment]].<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref> [[Herpes simplex virus]]<ref name=":2">{{Cite journal|date=2006-12-13|title=Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation|url=https://www.sciencedirect.com/science/article/pii/S0006899306029246|journal=Brain Research|language=en|volume=1125|issue=1|pages=155–162|doi=10.1016/j.brainres.2006.09.093|issn=0006-8993}}</ref>, [[Human herpesvirus 6|HHV-6]]<ref>{{Cite journal|date=2014-11-01|title=Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures|url=https://www.sciencedirect.com/science/article/pii/S1341321X14002682|journal=Journal of Infection and Chemotherapy|language=en|volume=20|issue=11|pages=716–721|doi=10.1016/j.jiac.2014.07.017|issn=1341-321X}}</ref> and [[Coxsackie B]]<ref>{{Cite journal|last=De Palma|first=Armando M.|last2=Verbeken|first2=Erik|last3=Van Aelst|first3=Ilse|last4=Van den Steen|first4=Philippe E.|last5=Opdenakker|first5=Ghislain|last6=Neyts|first6=Johan|date=2008-12-05|title=Increased gelatinase B/matrix metalloproteinase 9 (MMP-9) activity in a murine model of acute coxsackievirus B4-induced pancreatitis|url=https://www.ncbi.nlm.nih.gov/pubmed/18929380|journal=Virology|volume=382|issue=1|pages=20–27|doi=10.1016/j.virol.2008.08.046|issn=1096-0341|pmid=18929380}}</ref><ref>{{Cite journal|date=2006-03-01|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.sciencedirect.com/science/article/pii/S1054880705001729|journal=Cardiovascular Pathology|language=en|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807}}</ref> infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.<ref name=":2" /><ref>{{Cite journal|last=Zeng|first=Z. S.|last2=Cohen|first2=A. M.|last3=Guillem|first3=J. G.|date=May 1999|title=Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis|url=https://www.ncbi.nlm.nih.gov/pubmed/10334190|journal=Carcinogenesis|volume=20|issue=5|pages=749–755|issn=0143-3334|pmid=10334190}}</ref><ref>{{Cite journal|last=Van den Steen|first=Philippe E.|last2=Dubois|first2=Bénédicte|last3=Nelissen|first3=Inge|last4=Rudd|first4=Pauline M.|last5=Dwek|first5=Raymond A.|last6=Opdenakker|first6=Ghislain|date=Jan 2002|title=Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)|url=https://www.tandfonline.com/doi/abs/10.1080/10409230290771546|journal=Critical Reviews in Biochemistry and Molecular Biology|language=en|volume=37|issue=6|pages=375–536|doi=10.1080/10409230290771546|issn=1040-9238}}</ref> Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.<ref>{{Cite journal|last=Cheung|first=Caroline|last2=Luo|first2=Honglin|last3=Yanagawa|first3=Bobby|last4=Leong|first4=Hon Sing|last5=Samarasekera|first5=Dinesh|last6=Lai|first6=John C. K.|last7=Suarez|first7=Agripina|last8=Zhang|first8=Jingchun|last9=McManus|first9=Bruce M.|date=Mar 2006|title=Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/16533694|journal=Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology|volume=15|issue=2|pages=63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807|pmid=16533694}}</ref><ref>{{Cite journal|last=Meng|first=Xiao-hui|last2=Wang|first2=Yi|last3=Zhuang|first3=Jian-xin|last4=Han|first4=Xiu-zhen|last5=Chen|first5=Yao|last6=Jin|first6=You-peng|last7=Wang|first7=Yu-lin|last8=Yu|first8=Yong-hui|last9=Spires|first9=James P.|date=Aug 2004|title=Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis|url=https://www.ncbi.nlm.nih.gov/pubmed/15361294|journal=Chinese Medical Journal|volume=117|issue=8|pages=1195–1199|issn=0366-6999|pmid=15361294}}</ref><ref>{{Cite journal|last=Rutschow|first=Susanne|last2=Leschka|first2=Sebastian|last3=Westermann|first3=Dirk|last4=Puhl|first4=Kerstin|last5=Weitz|first5=Anneke|last6=Ladyszenskij|first6=Leonid|last7=Jaeger|first7=Sebastian|last8=Zeichhardt|first8=Heinz|last9=Noutsias|first9=Michel|date=2010-03-25|title=Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis--ongoing inflammation and an imbalance of the matrix degrading system|url=https://www.ncbi.nlm.nih.gov/pubmed/20035743|journal=European Journal of Pharmacology|volume=630|issue=1-3|pages=145–151|doi=10.1016/j.ejphar.2009.12.019|issn=1879-0712|pmid=20035743}}</ref>  
Infection can degrade collagen via direct secretion<ref name=":1">{{Cite journal | last = Harrington | first = DJ | date = Jun 1996 | title = Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease. | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC174012/ | journal = Infection and Immunity|volume=64 | issue = 6 | pages = 1885–1891|issn=0019-9567|pmid=8675283}}</ref> of collagenases and other [[Enzyme|enzymes]] (in the case of [[bacteria]]) or increased host production of [[Matrix metalloproteinase|matrix metalloproteinases]] (MMPs) as part of the normal [[immune system|immune response]] (in the case of bacteria and [[Virus|viruses]]). Numerous bacteria secrete their own [[collagenase]]s.<ref name=":1" /><ref>{{Cite journal | last = Duarte | first = Ana Sofia | last2 = Correia | first2 = Antonio | last3 = Esteves | first3 = Ana Cristina | date = 2016 | title = Bacterial collagenases - A review | url =https://www.ncbi.nlm.nih.gov/pubmed/24754251 | journal = Critical Reviews in Microbiology|volume=42 | issue = 1 | pages = 106–126 |doi=10.3109/1040841X.2014.904270|issn=1549-7828|pmid=24754251}}</ref> [[Borrelia]] spirochetes upregulate production of human collagenase (MMP-1) and gelatinase B (MMP-9)<ref>{{Cite journal | last = Gebbia | first = Joseph A. | last2 = Coleman | first2 = James L. | last3 = Benach | first3 = Jorge L. | date = 2001-01-01 | title = Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells |url =https://iai.asm.org/content/69/1/456 | journal = Infection and Immunity|language=en|volume=69 | issue = 1 | pages = 456–462|doi=10.1128/IAI.69.1.456-462.2001|issn=0019-9567|pmid=11119537}}</ref>, an enzyme that can degrade both [[elastin]] and partially hydrolyzed collagen.<ref name="Baker2009">{{Cite book | title = Comprehensive Vascular and Endovascular Surgery | date = 2009 | url=https://www.sciencedirect.com/science/article/pii/B9780323057264000299 | pages = 465–472 | last = Baxter | first = B. Timothy | author-link= | last2 = MacTaggart | first2 = Jason | author-link2 = |isbn=978-0-323-05726-4|chapter=Pathogenesis of Aortic Aneurysms|language=en|edition=2nd|location=Philadelphia|publisher=Mosby|editor-last=Hallett|editor-first=John W.|editor2-last=Mills|editor2-first=Joseph L.|editor3-last=Earnshaw|editor3-first=Jonothan J.|editor4-last=Reekers|editor4-first=Jim A.|editor5-last=Rooke|editor5-first=Thom W.|doi=10.1016/b978-0-323-05726-4.00029-9|pmc=|pmid=|access-date=|quote=|via=}}</ref> Borrelia infection has been associated with damage to collagen and elastin fibres, causing "spontaneous ruptures of tendons after slight strain, dislocation of vertebrae and an accumulation of prolapsed intervertebral discs as well as ossification of tendon insertions."<ref>{{Cite journal | last = Müller | first = Kurt E | date = 2012-12-31 | title = Damage of Collagen and Elastic Fibres by Borrelia Burgdorferi – Known and New Clinical and Histopathological Aspects |url =https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751012/ | journal = The Open Neurology Journal|volume=6 | pages = 179–186|doi=10.2174/1874205X01206010179|issn=1874-205X|pmc=3751012|pmid=23986790}}</ref> MMP-8 and MMP-9 are upregulated in bacterial [[meningitis]] and the latter is associated with an increased risk of [[blood-brain barrier]] breakdown and neurological sequale such as [[epilepsy]] and [[cognitive dysfunction]].<ref>{{Cite journal | last = Tiveron | first = Marcos Gradim | last2 = Pomerantzeff | first2 = Pablo Maria Alberto | last3 = de Lourdes Higuchi | first3 = Maria | last4 = Reis | first4 = Marcia Martins | last5 = de Jesus Pereira | first5 = Jaqueline | last6 = Kawakami | first6 = Joyce Tieko | last7 = Ikegami | first7 = Renata Nishiyama | last8 = de Almeida Brandao | first8 = Carlos Manuel | last9 = Jatene | first9 = Fabio Biscegli | date = 2017-04-21 | title = Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study | url = https://www.ncbi.nlm.nih.gov/pubmed/28431520 | journal = BMC infectious diseases|volume=17 | issue = 1 | pages = 297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref> [[Herpes simplex virus]]<ref name=":2">{{Cite journal | date = 2006-12-13 | title = Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation | url =https://www.sciencedirect.com/science/article/pii/S0006899306029246 | journal = Brain Research|language=en|volume=1125 | issue = 1 | pages = 155–162|doi=10.1016/j.brainres.2006.09.093|issn=0006-8993}}</ref>, [[Human herpesvirus 6|HHV-6]]<ref>{{Cite journal | date = 2014-11-01 | title = Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures |url =https://www.sciencedirect.com/science/article/pii/S1341321X14002682 | journal = Journal of Infection and Chemotherapy|language=en|volume=20 | issue = 11 | pages = 716–721|doi=10.1016/j.jiac.2014.07.017|issn=1341-321X}}</ref> and [[Coxsackie B]]<ref>{{Cite journal | last = De Palma | first = Armando M. | last2 = Verbeken | first2 = Erik | last3 = Van Aelst | first3 = Ilse | last4 = Van den Steen | first4 = Philippe E. | last5 = Opdenakker | first5 = Ghislain | last6 = Neyts | first6 = Johan | date = 2008-12-05 | title = Increased gelatinase B/matrix metalloproteinase 9 (MMP-9) activity in a murine model of acute coxsackievirus B4-induced pancreatitis |url =https://www.ncbi.nlm.nih.gov/pubmed/18929380 | journal = Virology|volume=382 | issue = 1 | pages = 20–27|doi=10.1016/j.virol.2008.08.046|issn=1096-0341|pmid=18929380}}</ref><ref>{{Cite journal | date = 2006-03-01 | title = Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis |url =https://www.sciencedirect.com/science/article/pii/S1054880705001729 | journal = Cardiovascular Pathology|language=en|volume=15 | issue = 2 | pages = 63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807}}</ref> infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.<ref name=":2" /><ref>{{Cite journal | last = Zeng|first = Z.S. | last2 = Cohen | first2 = A.M. | last3 = Guillem | first3 = J.G. | date = May 1999 | title = Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis |url =https://www.ncbi.nlm.nih.gov/pubmed/10334190 | journal = Carcinogenesis|volume=20 | issue = 5 | pages = 749–755|issn=0143-3334|pmid=10334190}}</ref><ref>{{Cite journal | last = Van den Steen | first = Philippe E. | last2 = Dubois | first2 = Bénédicte | last3 = Nelissen | first3 = Inge | last4 = Rudd | first4 = Pauline M. | last5 = Dwek | first5 = Raymond A. | last6 = Opdenakker | first6 = Ghislain | date = Jan 2002 | title = Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9) | url = https://www.tandfonline.com/doi/abs/10.1080/10409230290771546 | journal = Critical Reviews in Biochemistry and Molecular Biology|language=en|volume=37 | issue = 6 | pages = 375–536|doi=10.1080/10409230290771546|issn=1040-9238}}</ref> Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.<ref>{{Cite journal | last = Cheung|first = Caroline | last2 = Luo | first2 = Honglin | last3 = Yanagawa | first3 = Bobby | last4 = Leong | first4 = Hon Sing | last5 = Samarasekera | first5 = Dinesh | last6 = Lai | first6 = John C.K. | last7 = Suarez | first7 = Agripina | last8 = Zhang | first8 = Jingchun | last9 = McManus | first9 = Bruce M. | date = Mar 2006 | title = Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis |url =https://www.ncbi.nlm.nih.gov/pubmed/16533694 | journal = Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology|volume=15 | issue = 2 | pages = 63–74|doi=10.1016/j.carpath.2005.11.008|issn=1054-8807|pmid=16533694}}</ref><ref>{{Cite journal | last = Meng|first = Xiao-hui | last2 = Wang | first2 = Yi | last3 = Zhuang | first3 = Jian-xin | last4 = Han | first4 = Xiu-zhen | last5 = Chen | first5 = Yao | last6 = Jin | first6 = You-peng | last7 = Wang | first7 = Yu-lin | last8 = Yu | first8 = Yong-hui | last9 = Spires | first9 = James P. | date = Aug 2004 | title = Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis |url =https://www.ncbi.nlm.nih.gov/pubmed/15361294 | journal = Chinese Medical Journal|volume=117 | issue = 8 | pages = 1195–1199|issn=0366-6999|pmid=15361294}}</ref><ref>{{Cite journal | last = Rutschow|first = Susanne | last2 = Leschka | first2 = Sebastian | last3 = Westermann | first3 = Dirk | last4 = Puhl | first4 = Kerstin | last5 = Weitz | first5 = Anneke | last6 = Ladyszenskij | first6 = Leonid | last7 = Jaeger | first7 = Sebastian | last8 = Zeichhardt | first8 = Heinz | last9 = Noutsias | first9 = Michel | date = 2010-03-25 | title = Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis--ongoing inflammation and an imbalance of the matrix degrading system | url = https://www.ncbi.nlm.nih.gov/pubmed/20035743 | journal = European Journal of Pharmacology|volume=630 | issue = 1-3 | pages = 145–151|doi=10.1016/j.ejphar.2009.12.019|issn=1879-0712|pmid=20035743}}</ref>  
==== Infection and Ehlers-Danlos Syndrome ====
==== Infection and Ehlers-Danlos Syndromes ====
[[Ehlers-Danlos syndrome|Ehlers-Danlos Syndrome]] is a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, [[hypermobile EDS]] (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella.<ref name=":0">{{Cite journal|last=Mozayeni|first=Bobak Robert|last2=Maggi|first2=Ricardo Guillermo|last3=Bradley|first3=Julie Meredith|last4=Breitschwerdt|first4=Edward Bealmear|date=Apr 2018|title=Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias|url=https://journals.lww.com/md-journal/Pages/articleviewer.aspx?year=2018&issue=04270&article=00032&type=Fulltext|journal=Medicine|language=en-US|volume=97|issue=17|pages=e0465|doi=10.1097/MD.0000000000010465|issn=0025-7974}}</ref> [[Mycoplasma pneumoniae]] has been associated with [[mitral valve]] degeneration, a complication of EDS.<ref>{{Cite journal|last=Tiveron|first=Marcos Gradim|last2=Pomerantzeff|first2=Pablo Maria Alberto|last3=de Lourdes Higuchi|first3=Maria|last4=Reis|first4=Marcia Martins|last5=de Jesus Pereira|first5=Jaqueline|last6=Kawakami|first6=Joyce Tieko|last7=Ikegami|first7=Renata Nishiyama|last8=de Almeida Brandao|first8=Carlos Manuel|last9=Jatene|first9=Fabio Biscegli|date=2017-04-21|title=Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study|url=https://www.ncbi.nlm.nih.gov/pubmed/28431520|journal=BMC infectious diseases|volume=17|issue=1|pages=297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref>
[[Ehlers-Danlos syndrome|Ehlers-Danlos Syndromes]] are a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, [[hypermobile EDS]] (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella.<ref name=":0">{{Cite journal | last = Mozayeni|first = Bobak Robert | last2 = Maggi | first2 = Ricardo Guillermo | last3 = Bradley | first3 = Julie Meredith | last4 = Breitschwerdt | first4 = Edward Bealmear | date = Apr 2018 | title = Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias |url =https://journals.lww.com/md-journal/Pages/articleviewer.aspx?year=2018&issue=04270&article=00032&type=Fulltext | journal = Medicine|language=en-US|volume=97 | issue = 17| pages = e0465|doi=10.1097/MD.0000000000010465|issn=0025-7974}}</ref> [[Mycoplasma pneumoniae]] has been associated with mitral valve degeneration, a complication of EDS.<ref>{{Cite journal | last = Tiveron | first = Marcos Gradim | last2 = Pomerantzeff | first2 = Pablo Maria Alberto | last3 = de Lourdes Higuchi | first3 = Maria | last4 = Reis | first4 = Marcia Martins | last5 = de Jesus Pereira | first5 = Jaqueline | last6 = Kawakami | first6 = Joyce Tieko | last7 = Ikegami | first7 = Renata Nishiyama | last8 = de Almeida Brandao | first8 = Carlos Manuel | last9 = Jatene | first9 = Fabio Biscegli | date = 2017-04-21 | title = Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study | url = https://www.ncbi.nlm.nih.gov/pubmed/28431520 | journal = BMC infectious diseases|volume=17 | issue = 1 | pages = 297|doi=10.1186/s12879-017-2387-8|issn=1471-2334|pmc=5399830|pmid=28431520}}</ref>


=== Fluoroquinolone antibiotics ===
=== Fluoroquinolone antibiotics ===
“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”<ref>{{Cite web|url=https://www.jwatch.org/na48248/2019/02/13/adverse-effects-fluoroquinolones-where-do-we-stand|title=NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals|website=www.jwatch.org|access-date=2019-06-18}}</ref> A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.<ref>{{Cite journal|last=Redelmeier|first=Donald A.|last2=Lu|first2=Hong|last3=Daneman|first3=Nick|date=2015-11-01|title=Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study|url=https://bmjopen.bmj.com/content/5/11/e010077|journal=BMJ Open|language=en|volume=5|issue=11|pages=e010077|doi=10.1136/bmjopen-2015-010077|issn=2044-6055|pmid=26582407}}</ref> In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.<ref>{{Cite journal|last=Research|first=Center for Drug Evaluation and|date=2019-04-15|title=FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients|url=http://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics|journal=FDA|language=en}}</ref>  
“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”<ref>{{Cite web | url = https://www.jwatch.org/na48248/2019/02/13/adverse-effects-fluoroquinolones-where-do-we-stand | title = NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals | website = jwatch.org|access-date=2019-06-18}}</ref> A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.<ref>{{Cite journal | last = Redelmeier | first = Donald A. | last2 = Lu | first2 = Hong | last3 = Daneman | first3 = Nick | date = 2015-11-01 | title = Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study | url = https://bmjopen.bmj.com/content/5/11/e010077 | journal = BMJ Open|language=en|volume=5 | issue = 11| pages = e010077|doi=10.1136/bmjopen-2015-010077|issn=2044-6055|pmid=26582407}}</ref> In December 2018, the FDA recommended against its use in patients with connective tissue disorders like [[Ehlers-Danlos Syndrome]] and Marfan Syndrome.<ref>{{Cite journal | last = Research|first = Center for Drug Evaluation and | date = 2019-04-15 | title = FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients |url =http://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-increased-risk-ruptures-or-tears-aorta-blood-vessel-fluoroquinolone-antibiotics | journal = FDA|language=en}}</ref>  


[[Doxycycline]], by contrast, inhibits MMP production.<ref name=":02">{{Cite journal|last=De Paiva|first=Cintia S.|last2=Corrales|first2=Rosa M.|last3=Villarreal|first3=Arturo L.|last4=Farley|first4=William J.|last5=Li|first5=De-Quan|last6=Stern|first6=Michael E.|last7=Pflugfelder|first7=Stephen C.|date=2006-09-01|title=Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye|url=http://www.sciencedirect.com/science/article/pii/S0014483506001709|journal=Experimental Eye Research|volume=83|issue=3|pages=526–535|doi=10.1016/j.exer.2006.02.004|issn=0014-4835}}</ref><ref>{{Cite journal|last=Roach|first=D. M|last2=Fitridge|first2=R. A|last3=Laws|first3=P. E|last4=Millard|first4=S. H|last5=Varelias|first5=A|last6=Cowled|first6=P. A|date=2002-03-01|title=Up-regulation of MMP-2 and MMP-9 Leads to Degradation of Type IV Collagen During Skeletal Muscle Reperfusion Injury; Protection by the MMP Inhibitor, Doxycycline|url=http://www.sciencedirect.com/science/article/pii/S1078588402915984|journal=European Journal of Vascular and Endovascular Surgery|volume=23|issue=3|pages=260–269|doi=10.1053/ejvs.2002.1598|issn=1078-5884}}</ref><ref>{{Cite journal|last=Niedzwiecki|first=A.|last2=Rath|first2=M.|last3=Kalinovsky|first3=T.|last4=Monterrey|first4=J. C.|last5=Roomi|first5=M. W.|date=2010-03-01|title=In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors|url=http://www.spandidos-publications.com/or/23/3/605/abstract|journal=Oncology Reports|volume=23|issue=3|pages=605–614|doi=10.3892/or_00000675|issn=1021-335X}}</ref><ref>{{Cite journal|last=Choi|first=Dong-Hoon|last2=Moon|first2=Ik-Sang|last3=Choi|first3=Bong-Kyu|last4=Paik|first4=Jeong-Won|last5=Kim|first5=Yoon-Sik|last6=Choi|first6=Seong-Ho|last7=Kim|first7=Chong-Kwan|date=2004|title=Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.2004.00696.x|journal=Journal of Periodontal Research|language=en|volume=39|issue=1|pages=20–26|doi=10.1111/j.1600-0765.2004.00696.x|issn=1600-0765}}</ref><ref>{{Cite journal|last=Li|first=De-Quan|last2=Lokeshwar|first2=Balakrishna L|last3=Solomon|first3=Abraham|last4=Monroy|first4=Dagoberto|last5=Ji|first5=Zhonghua|last6=Pflugfelder|first6=Stephen C|date=2001-10-01|title=Regulation of MMP-9 Production by Human Corneal Epithelial Cells|url=http://www.sciencedirect.com/science/article/pii/S0014483501910541|journal=Experimental Eye Research|volume=73|issue=4|pages=449–459|doi=10.1006/exer.2001.1054|issn=0014-4835}}</ref><ref>{{Cite journal|last=Brown David L.|last2=Desai Kavita K.|last3=Vakili Babak A.|last4=Nouneh Chadi|last5=Lee Hsi-Ming|last6=Golub Lorne M.|date=2004-04-01|title=Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial|url=https://www.ahajournals.org/doi/full/10.1161/01.ATV.0000121571.78696.dc|journal=Arteriosclerosis, Thrombosis, and Vascular Biology|volume=24|issue=4|pages=733–738|doi=10.1161/01.ATV.0000121571.78696.dc}}</ref>
[[Doxycycline]], by contrast, inhibits MMP production.<ref name=":02">{{Cite journal | last = De Paiva | first = Cintia S. | last2 = Corrales | first2 = Rosa M. | last3 = Villarreal | first3 = Arturo L. | last4 = Farley | first4 = William J. | last5 = Li | first5 = De-Quan | last6 = Stern | first6 = Michael E. | last7 = Pflugfelder | first7 = Stephen C. | date = 2006-09-01 | title = Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye | url =http://www.sciencedirect.com/science/article/pii/S0014483506001709 | journal = Experimental Eye Research|volume=83 | issue = 3 | pages = 526–535|doi=10.1016/j.exer.2006.02.004|issn=0014-4835}}</ref><ref>{{Cite journal | last = Roach|first = D. M | last2 = Fitridge | first2 = R. A | last3 = Laws | first3 = P. E | last4 = Millard | first4 = S. H | last5 = Varelias | first5 = A | last6 = Cowled | first6 = P. A | date = 2002-03-01 | title = Up-regulation of MMP-2 and MMP-9 Leads to Degradation of Type IV Collagen During Skeletal Muscle Reperfusion Injury; Protection by the MMP Inhibitor, Doxycycline | url =http://www.sciencedirect.com/science/article/pii/S1078588402915984 | journal = European Journal of Vascular and Endovascular Surgery|volume=23 | issue = 3 | pages = 260–269|doi=10.1053/ejvs.2002.1598|issn=1078-5884}}</ref><ref>{{Cite journal | last = Niedzwiecki|first = A. | last2 = Rath | first2 = M. | last3 = Kalinovsky | first3 = T. | last4 = Monterrey | first4 = J.C. | last5 = Roomi | first5 = M.W. | date = 2010-03-01 | title = In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors |url =http://www.spandidos-publications.com/or/23/3/605/abstract | journal = Oncology Reports|volume=23 | issue = 3 | pages = 605–614|doi=10.3892/or_00000675|issn=1021-335X}}</ref><ref>{{Cite journal | last = Choi|first = Dong-Hoon | last2 = Moon | first2 = Ik-Sang | last3 = Choi | first3 = Bong-Kyu | last4 = Paik | first4 = Jeong-Won | last5 = Kim | first5 = Yoon-Sik | last6 = Choi | first6 = Seong-Ho | last7 = Kim | first7 = Chong-Kwan | date = 2004 | title = Effects of sub-antimicrobial dose doxycycline therapy on crevicular fluid MMP-8, and gingival tissue MMP-9, TIMP-1 and IL-6 levels in chronic periodontitis |url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0765.2004.00696.x | journal = Journal of Periodontal Research|language=en|volume=39 | issue = 1 | pages = 20–26|doi=10.1111/j.1600-0765.2004.00696.x|issn=1600-0765}}</ref><ref>{{Cite journal | last = Li|first = De-Quan | last2 = Lokeshwar | first2 = Balakrishna L | last3 = Solomon | first3 = Abraham | last4 = Monroy | first4 = Dagoberto | last5 = Ji | first5 = Zhonghua | last6 = Pflugfelder | first6 = Stephen C | date = 2001-10-01 | title = Regulation of MMP-9 Production by Human Corneal Epithelial Cells |url =http://www.sciencedirect.com/science/article/pii/S0014483501910541 | journal = Experimental Eye Research|volume=73 | issue = 4 | pages = 449–459|doi=10.1006/exer.2001.1054|issn=0014-4835}}</ref><ref>{{Cite journal | last = Brown David L. | last2 = Desai Kavita K. | last3 = Vakili Babak A. | last4 = Nouneh Chadi | last5 = Lee Hsi-Ming | last6 = Golub Lorne M. | date = 2004-04-01 | title = Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial | url = https://www.ahajournals.org/doi/full/10.1161/01.ATV.0000121571.78696.dc | journal = Arteriosclerosis, Thrombosis, and Vascular Biology|volume=24 | issue = 4 | pages = 733–738|doi=10.1161/01.ATV.0000121571.78696.dc}}</ref>


=== Mold ===
=== Mold ===
''[[Stachybotrys chartarum]]'' (black [[mold]]) release proteinases that can hydrolyze [[gelatin]] and collagen I and IV.<ref>{{Cite journal|last=Yike|first=Iwona|last2=Rand|first2=Thomas|last3=Dearborn|first3=Dorr G.|date=2007-07-03|title=The role of fungal proteinases in pathophysiology of Stachybotrys chartarum|url=https://doi.org/10.1007/s11046-007-9037-4|journal=Mycopathologia|language=en|volume=164|issue=4|pages=171|doi=10.1007/s11046-007-9037-4|issn=1573-0832}}</ref> Three [[Mycotoxin|mycotoxins]], deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of [[aggrecan]] and type II collagen. Selenium partially inhibited the effects of these mycotoxins.<ref>{{Cite journal|last=Caterson|first=Bruce|last2=Li|first2=Jin|last3=Wang|first3=Jiali|last4=Luo|first4=Mingxiu|last5=Liu|first5=Jiayuan|last6=Zhang|first6=Zengtie|last7=Fu|first7=Qiang|last8=Chen|first8=Jinghong|last9=Li|first9=Siyuan|date=2012|title=The Effects of Mycotoxins and Selenium Deficiency on Tissue-Engineered Cartilage|url=https://www.karger.com/Article/FullText/335046|journal=Cells Tissues Organs|language=english|volume=196|issue=3|pages=241–250|doi=10.1159/000335046|issn=1422-6405|pmid=22538829}}</ref>
''[[Stachybotrys chartarum]]'' (black [[mold]]) release proteinases that can hydrolyze gelatin and collagen I and IV.<ref>{{Cite journal | last = Yike | first = Iwona | last2 = Rand | first2 = Thomas | last3 = Dearborn | first3 = Dorr G. | date = 2007-07-03 | title = The role of fungal proteinases in pathophysiology of Stachybotrys chartarum | url = https://doi.org/10.1007/s11046-007-9037-4 | journal = Mycopathologia|language=en|volume=164 | issue = 4 | pages = 171|doi=10.1007/s11046-007-9037-4|issn=1573-0832}}</ref> Three Mycotoxins, deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of [[aggrecan]] and type II collagen. Selenium partially inhibited the effects of these mycotoxins.<ref>{{Cite journal | last = Caterson | first = Bruce | last2 = Li | first2 = Jin | last3 = Wang | first3 = Jiali | last4 = Luo | first4 = Mingxiu | last5 = Liu | first5 = Jiayuan | last6 = Zhang | first6 = Zengtie | last7 = Fu | first7 = Qiang | last8 = Chen | first8 = Jinghong | last9 = Li | first9 = Siyuan | date = 2012 | title = The Effects of Mycotoxins and Selenium Deficiency on Tissue-Engineered Cartilage | url =https://www.karger.com/Article/FullText/335046 | journal = Cells Tissues Organs|language=en|volume=196 | issue = 3 | pages = 241–250|doi=10.1159/000335046|issn=1422-6405|pmid=22538829}}</ref>


=== Sex hormones ===
=== Sex hormones ===
Several animal studies of collagen in muscle and the aorta have found that [[estrogen]] decreases and [[testosterone]] collagen and elastin.<ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1977-06-01|title=Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats|url=https://www.physiology.org/doi/abs/10.1152/ajpheart.1977.232.6.H617|journal=American Journal of Physiology-Heart and Circulatory Physiology|volume=232|issue=6|pages=H617–H621|doi=10.1152/ajpheart.1977.232.6.H617|issn=0363-6135}}</ref><ref>{{Cite journal|last=Cembrano|first=JosÉ|last2=Lillo|first2=Manuel|last3=Val|first3=JosÉ|last4=Mardones|first4=Jorge|date=1960-05-01|title=Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens|url=http://insights.ovid.com/|journal=Circulation Research|language=ENGLISH|volume=8|issue=3|pages=527–529|issn=0009-7330|pmid=13808759}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|last2=Swain|first2=Margaret L.|date=1980-08-01|title=Influence of contraceptive and other sex steroids on aortic collagen and elastin|url=http://www.sciencedirect.com/science/article/pii/0014480080900039|journal=Experimental and Molecular Pathology|volume=33|issue=1|pages=15–24|doi=10.1016/0014-4800(80)90003-9|issn=0014-4800}}</ref><ref>{{Cite journal|last=Fischer|first=G. M.|last2=Swain|first2=M. L.|date=1985-02-01|title=Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas|url=http://www.sciencedirect.com/science/article/pii/0021915085901777|journal=Atherosclerosis|volume=54|issue=2|pages=177–185|doi=10.1016/0021-9150(85)90177-7|issn=0021-9150}}</ref><ref>{{Cite journal|last=Fischer|first=Grace M.|date=1972-11-01|title=In Vivo EflEects of Estradiol on Collagen and Elastin Dynamics in Rat Aorta|url=https://academic.oup.com/endo/article/91/5/1227/2621144|journal=Endocrinology|language=en|volume=91|issue=5|pages=1227–1232|doi=10.1210/endo-91-5-1227|issn=0013-7227}}</ref> A study of collagen in male cows found that collagen synthesis increased with puberty, possibly as a result of testosterone.<ref>{{Cite journal|last=Cross|first=H. R.|last2=Schanbacher|first2=B. D.|last3=Crouse|first3=J. D.|date=1984-01-01|title=Sex, age and breed related changes in bovine testosterone and intramuscular collagen|url=http://www.sciencedirect.com/science/article/pii/0309174084900214|journal=Meat Science|volume=10|issue=3|pages=187–195|doi=10.1016/0309-1740(84)90021-4|issn=0309-1740}}</ref> Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).<ref>{{Cite journal|last=Judge|first=M. D.|last2=Diekman|first2=M. A.|last3=Lemenager|first3=R. P.|last4=Aberle|first4=E. D.|last5=Jones|first5=S. J.|last6=Gerrard|first6=D. E.|date=1987-11-01|title=Collagen Stability, Testosterone Secretion and Meat Tenderness in Growing Bulls and Steers|url=https://academic.oup.com/jas/article/65/5/1236/4662470|journal=Journal of Animal Science|language=en|volume=65|issue=5|pages=1236–1242|doi=10.2527/jas1987.6551236x|issn=0021-8812}}</ref> An ''in vitro'' study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.<ref>{{Cite journal|last=Boyan|first=B. D.|last2=Soskolne|first2=W. A.|last3=Brooks|first3=B. P.|last4=Ornoy|first4=A.|last5=Nasatzky|first5=E.|last6=Schwartz|first6=Z.|date=1994-04-01|title=Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture|url=https://academic.oup.com/endo/article/134/4/1640/3035468|journal=Endocrinology|language=en|volume=134|issue=4|pages=1640–1647|doi=10.1210/endo.134.4.8137726|issn=0013-7227}}</ref>     
Several animal studies of collagen in muscle and the aorta have found that [[estrogen]] decreases and [[testosterone]] increases collagen and elastin.<ref>{{Cite journal | last = Fischer | first = G.M. | last2 = Swain | first2 = M.L. | date = 1977-06-01 | title = Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats |url =https://www.physiology.org/doi/abs/10.1152/ajpheart.1977.232.6.H617 | journal = American Journal of Physiology-Heart and Circulatory Physiology|volume=232 | issue = 6| pages=H617–H621|doi=10.1152/ajpheart.1977.232.6.H617|issn=0363-6135}}</ref><ref>{{Cite journal | last = Cembrano|first = JosÉ | last2 = Lillo | first2 = Manuel | last3 = Val | first3 = JosÉ | last4 = Mardones | first4 = Jorge | date = 1960-05-01 | title = Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens |url =http://insights.ovid.com/ | journal = Circulation Research|language=ENGLISH|volume=8 | issue = 3 | pages = 527–529|issn=0009-7330|pmid=13808759}}</ref><ref>{{Cite journal | last = Fischer | first = Grace M. | last2 = Swain | first2 = Margaret L. | date = 1980-08-01 | title = Influence of contraceptive and other sex steroids on aortic collagen and elastin | url =http://www.sciencedirect.com/science/article/pii/0014480080900039 | journal = Experimental and Molecular Pathology|volume=33 | issue = 1 | pages = 15–24|doi=10.1016/0014-4800(80)90003-9|issn=0014-4800}}</ref><ref>{{Cite journal | last = Fischer | first = G.M. | last2 = Swain | first2 = M.L. | date = 1985-02-01 | title = Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas |url =http://www.sciencedirect.com/science/article/pii/0021915085901777 | journal = Atherosclerosis|volume=54 | issue = 2 | pages = 177–185|doi=10.1016/0021-9150(85)90177-7|issn=0021-9150}}</ref><ref>{{Cite journal | last = Fischer | first = Grace M. | date = 1972-11-01 | title = In Vivo EflEects of Estradiol on Collagen and Elastin Dynamics in Rat Aorta | url = https://academic.oup.com/endo/article/91/5/1227/2621144 | journal = Endocrinology|language=en|volume=91 | issue = 5 | pages = 1227–1232|doi=10.1210/endo-91-5-1227|issn=0013-7227}}</ref> A study of collagen in male cattle found that collagen synthesis increased with puberty, possibly as a result of testosterone.<ref>{{Cite journal | last = Cross | first = H.R. | last2 = Schanbacher | first2 = B.D. | last3 = Crouse | first3 = J.D. | date = 1984-01-01 | title = Sex, age and breed related changes in bovine testosterone and intramuscular collagen | url =http://www.sciencedirect.com/science/article/pii/0309174084900214 | journal = Meat Science|volume=10 | issue = 3 | pages = 187–195|doi=10.1016/0309-1740(84)90021-4|issn=0309-1740}}</ref> Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).<ref>{{Cite journal | last = Judge | first = M.D. | last2 = Diekman | first2 = M.A. | last3 = Lemenager | first3 = R.P. | last4 = Aberle | first4 = E.D. | last5 = Jones | first5 = S.J. | last6 = Gerrard | first6 = D.E. | date = 1987-11-01 | title = Collagen Stability, Testosterone Secretion and Meat Tenderness in Growing Bulls and Steers |url =https://academic.oup.com/jas/article/65/5/1236/4662470 | journal = Journal of Animal Science|language=en|volume=65 | issue = 5 | pages = 1236–1242|doi=10.2527/jas1987.6551236x|issn=0021-8812}}</ref> An ''in vitro'' study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.<ref>{{Cite journal | last = Boyan | first = B.D. | last2 = Soskolne | first2 = W.A. | last3 = Brooks | first3 = B.P. | last4 = Ornoy | first4 = A. | last5 = Nasatzky | first5 = E. | last6 = Schwartz | first6 = Z. | date = 1994-04-01 | title = Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture | url =https://academic.oup.com/endo/article/134/4/1640/3035468 | journal = Endocrinology|language=en|volume=134 | issue = 4 | pages = 1640–1647|doi=10.1210/endo.134.4.8137726|issn=0013-7227}}</ref>     


== In human disease ==
== In human disease ==
=== Ehlers-Danlos Syndrome ===
=== Ehlers-Danlos Syndrome ===
{{Main article|page_name=Ehlers-Danlos Syndrome}}
{{Main article| page_name=Ehlers-Danlos Syndrome}}


=== Mast cell activation syndrome ===
=== Mast cell activation syndrome ===
{{Main article|page_name=Mast cell activation syndrome}}
{{Main article| page_name=Mast cell activation syndrome}}


=== ME/CFS ===
=== ME/CFS ===
{{Main article|page_name=Myalgic encephalomyelitis}}
{{Main article| page_name=Myalgic encephalomyelitis}}


Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen that also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|date=Jan 2015|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|language=English|volume=3|pages=1|doi=10.2147/HP.S60872|issn=2324-1128}}</ref> The data are based on self-reported diagnosis of [[chronic fatigue syndrome]] and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.<ref>{{Cite news|url=https://mecfsresearchreview.me/2018/06/11/analysis-of-data-from-500000-individuals-in-uk-biobank-demonstrates-an-inherited-component-to-me-cfs/amp/?__twitter_impression=true|title=Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS|date=2018-06-11|work=ME/CFS Research Review|access-date=2018-11-11|language=en-US}}</ref>
Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal | last = Schneider | first = Martin | last2 = Harnoss | first2 = Jonathan Michael | last3 = Strowitzki | first3 = Moritz J. | last4 = Radhakrishnan | first4 = Praveen | last5 = Platzer | first5 = Lisa | last6 = Harnoss | first6 = Julian Camill | last7 = Hank | first7 = Thomas | last8 = Cai | first8 = Jun | last9 = Ulrich | first9 = Alexis | date = Jan 2015 | title = Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges |url =https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP | journal = Hypoxia|language=English|volume=3 | pages = 1|doi=10.2147/HP.S60872|issn=2324-1128}}</ref> The data are based on self-reported diagnosis of [[chronic fatigue syndrome]] and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.<ref>{{Cite news |url =https://mecfsresearchreview.me/2018/06/11/analysis-of-data-from-500000-individuals-in-uk-biobank-demonstrates-an-inherited-component-to-me-cfs/amp/?__twitter_impression=true | title = Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS | date = 2018-06-11|work=ME/CFS Research Review|access-date=2018-11-11|language=en-US}}</ref>


Elevated levels of [[hydroxyproline]], a marker of collagen breakdown, was found by [[Wenzhong Xiao]] in the [[Severely Ill Patient Study]].<ref>{{Citation|last=Open Medicine Foundation - OMF|title=Wenzhong Xiao, PhD {{!}} Results from the Severely Ill Patient Study (SIPS)|date=2018-11-07|url=https://www.youtube.com/watch?v=_N1o2gbaCl4&feature=youtu.be&t=853|access-date=2019-07-16}}</ref> [[Robert Naviaux]]’s work has suggested it as a possible [[Diagnostic biomarker|biomarker]] for female [[ME/CFS]] patients.<ref>{{Cite journal|last=Gordon|first=Eric|last2=Anderson|first2=Wayne|last3=Nathan|first3=Neil|last4=Baxter|first4=Asha|last5=Wang|first5=Lin|last6=Alaynick|first6=William A.|last7=Bright|first7=A. Taylor|last8=Li|first8=Kefeng|last9=Naviaux|first9=Jane C.|date=2016-09-13|title=Metabolic features of chronic fatigue syndrome|url=https://www.pnas.org/content/113/37/E5472|journal=Proceedings of the National Academy of Sciences|language=en|volume=113|issue=37|pages=E5472–E5480|doi=10.1073/pnas.1607571113|issn=0027-8424|pmid=27573827}}</ref> [[Maureen Hanson]] failed to find elevated hydroxyproline in her metabolomics study.{{Citation needed|reason=}}
Elevated levels of [[hydroxyproline]], a marker of collagen breakdown, was found by [[Wenzhong Xiao]] in the [[Severely Ill Patient Study]].<ref>{{Citation | last = Open Medicine Foundation - OMF | title = Wenzhong Xiao, PhD {{!}} Results from the Severely Ill Patient Study (SIPS) | date = 2018-11-07 | url = https://www.youtube.com/watch?v=_N1o2gbaCl4&feature=youtu.be&t=853|access-date=2019-07-16}}</ref> [[Robert Naviaux]]’s work has suggested it as a possible [[Diagnostic biomarker|biomarker]] for female [[ME/CFS]] patients.<ref name="Navauix2016">{{Cite journal | last1 = Naviaux | first1 = Robert K. | authorlink = Robert Naviaux | first2 = Jane C. | last2 = Naviaux | author-link2 = | last3 = Kefeng | first3 =Li | first4 =  A. Taylor | last4 = Bright | first5 = William A. | last5 = Alaynick | first6 = Lin | last6 = Wang | first7 = Asha | last7 = Baxter | first8 = Neil | last8 = Nathan | first9 = Wayne | last9 = Anderson | first10 = Eric | last10 = Gordon | date = 2016-09-13 | title = Metabolic features of chronic fatigue syndrome | url =https://www.pnas.org/content/113/37/E5472 | journal = Proceedings of the National Academy of Sciences|language=en|volume=113 | issue = 37| pages = E5472–E5480|doi=10.1073/pnas.1607571113|issn=0027-8424|pmid=27573827}}</ref> [[Maureen Hanson]] failed to find elevated hydroxyproline in her metabolomics study.{{Citation needed|reason=}}


==As a supplement==
==As a supplement==
When hydrolyzed, collagen is reduced to small [[peptide]]s, which can be ingested in the form of [[dietary supplement]] or [[functional food]]s and beverages with the intent to aid joint and bone health and enhance skin health.<ref>{{Cite journal|last=Guillerminet|first=Fanny|last2=Beaupied|first2=Hélène|last3=Fabien-Soulé|first3=Véronique|last4=Tomé|first4=Daniel|last5=Benhamou|first5=Claude-Laurent|last6=Roux|first6=Christian|last7=Blais|first7=Anne|date=2010-03-01|title=Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study|url=http://www.thebonejournal.com/article/S8756-3282(09)02003-1/abstract|journal=Bone|language=English|volume=46|issue=3|pages=827–834|doi=10.1016/j.bone.2009.10.035|issn=8756-3282}}</ref><ref>{{Cite journal|last=Guillerminet|first=F.|last2=Fabien-Soulé|first2=V.|last3=Even|first3=P. C.|last4=Tomé|first4=D.|last5=Benhamou|first5=C.-L.|last6=Roux|first6=C.|last7=Blais|first7=A.|date=2012-07-01|title=Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice|url=https://link.springer.com/article/10.1007/s00198-011-1788-6|journal=Osteoporosis International|language=en|volume=23|issue=7|pages=1909–1919|doi=10.1007/s00198-011-1788-6|issn=0937-941X}}</ref><ref>{{Cite journal|last=Daneault|first=A.|date=2014-04-01|title=Hydrolyzed collagen contributes to osteoblast differentiation in vitro and subsequent bone health in vivo|url=http://www.oarsijournal.com/article/S1063-4584(14)00280-5/fulltext|journal=Osteoarthritis and Cartilage|language=English|volume=22|pages=S131|doi=10.1016/j.joca.2014.02.240|issn=1063-4584}}</ref><ref>{{Cite journal|last=Daneault|first=Audrey|last2=Prawitt|first2=Janne|last3=Fabien Soulé|first3=Véronique|last4=Coxam|first4=Véronique|last5=Wittrant|first5=Yohann|date=2017-06-13|title=Biological effect of hydrolyzed collagen on bone metabolism|journal=Critical Reviews in Food Science and Nutrition|volume=57|issue=9|pages=1922–1937|doi=10.1080/10408398.2015.1038377|issn=1549-7852|pmid=25976422|url=https://zenodo.org/record/889529|deadurl=no|archiveurl=https://web.archive.org/web/20170913183348/https://zenodo.org/record/889529|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Jiang|first=J.X.|date=2014|title=Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study|url=http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|journal=Agro FOOD Indusrty Hi Tech|volume=25|pages=19–23|via=|deadurl=no|archiveurl=https://web.archive.org/web/20170913183401/http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|archivedate=2017-09-13|df=}}</ref><ref>{{Cite journal|last=Dar|first=Qurratul-Ain|last2=Schott|first2=Eric M.|last3=Catheline|first3=Sarah E.|last4=Maynard|first4=Robert D.|last5=Liu|first5=Zhaoyang|last6=Kamal|first6=Fadia|last7=Farnsworth|first7=Christopher W.|last8=Ketz|first8=John P.|last9=Mooney|first9=Robert A.|date=2017-04-06|title=Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis|url=http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174705|journal=PLOS ONE|volume=12|issue=4|pages=e0174705|doi=10.1371/journal.pone.0174705|issn=1932-6203|pmc=5383229|pmid=28384173|deadurl=no|archiveurl=https://web.archive.org/web/20170913184032/http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0174705|archivedate=2017-09-13|df=|bibcode=2017PLoSO..1274705D}}</ref><ref>{{Cite journal|last=Asserin|first=Jérome|last2=Lati|first2=Elian|last3=Shioya|first3=Toshiaki|last4=Prawitt|first4=Janne|date=2015-12-01|title=The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo‐controlled clinical trials|url=http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|journal=Journal of Cosmetic Dermatology|language=en|volume=14|issue=4|pages=291–301|doi=10.1111/jocd.12174|issn=1473-2165|deadurl=no|archiveurl=https://web.archive.org/web/20170910193750/http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|archivedate=2017-09-10|df=}}</ref> These [[hydroxyproline]]-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.<ref>{{Cite journal|last=Ichikawa|first=Satomi|last2=Morifuji|first2=Masashi|last3=Ohara|first3=Hiroki|last4=Matsumoto|first4=Hitoshi|last5=Takeuchi|first5=Yasuo|last6=Sato|first6=Kenji|date=2010-02-01|title=Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate|url=https://dx.doi.org/10.3109/09637480903257711|journal=International Journal of Food Sciences and Nutrition|volume=61|issue=1|pages=52–60|doi=10.3109/09637480903257711|issn=0963-7486|pmid=19961355}}</ref><ref>{{Cite journal|last=Shigemura|first=Yasutaka|last2=Kubomura|first2=Daiki|last3=Sato|first3=Yoshio|last4=Sato|first4=Kenji|date=2014-09-15|title=Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion|url=http://www.sciencedirect.com/science/article/pii/S0308814614002763|journal=Food Chemistry|volume=159|pages=328–332|doi=10.1016/j.foodchem.2014.02.091}}</ref><ref>{{Cite journal|last=Watanabe-Kamiyama|first=Mari|last2=Shimizu|first2=Muneshige|last3=Kamiyama|first3=Shin|last4=Taguchi|first4=Yasuki|last5=Sone|first5=Hideyuki|last6=Morimatsu|first6=Fumiki|last7=Shirakawa|first7=Hitoshi|last8=Furukawa|first8=Yuji|last9=Komai|first9=Michio|date=2010-01-27|title=Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats|url=https://dx.doi.org/10.1021/jf9031487|journal=Journal of Agricultural and Food Chemistry|volume=58|issue=2|pages=835–841|doi=10.1021/jf9031487|issn=0021-8561}}</ref>
When hydrolyzed, collagen is reduced to small peptides, which can be ingested in the form of dietary [[:Category:Supplements|supplement]] or [[:Category:Medicinal foods|functional food]]s and beverages with the intent to aid joint and bone health and enhance skin health.<ref>{{Cite journal | last = Guillerminet | first = Fanny | last2 = Beaupied | first2 = Hélène | last3 = Fabien-Soulé | first3 = Véronique | last4 = Tomé | first4 = Daniel | last5 = Benhamou | first5 = Claude-Laurent | last6 = Roux | first6 = Christian | last7 = Blais | first7 = Anne | date = 2010-03-01 | title = Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study | url = http://www.thebonejournal.com/article/S8756-3282(09)02003-1/abstract | journal = Bone|language=English|volume=46 | issue = 3 | pages = 827–834|doi=10.1016/j.bone.2009.10.035|issn=8756-3282}}</ref><ref>{{Cite journal | last = Guillerminet | first = F. | last2 = Fabien-Soulé | first2 = V. | last3 = Even | first3 = P.C. | last4 = Tomé | first4 = D. | last5 = Benhamou | first5 = C.-L. | last6 = Roux | first6 = C. | last7 = Blais | first7 = A. | date = 2012-07-01 | title = Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice | url =https://link.springer.com/article/10.1007/s00198-011-1788-6 | journal = Osteoporosis International|language=en|volume=23 | issue = 7 | pages = 1909–1919|doi=10.1007/s00198-011-1788-6|issn=0937-941X}}</ref><ref>{{Cite journal | last = Daneault | first = A. | date = 2014-04-01 | title = Hydrolyzed collagen contributes to osteoblast differentiation in vitro and subsequent bone health in vivo | url = http://www.oarsijournal.com/article/S1063-4584(14)00280-5/fulltext | journal = Osteoarthritis and Cartilage|language=English|volume=22| pages=S131|doi=10.1016/j.joca.2014.02.240|issn=1063-4584}}</ref><ref>{{Cite journal | last = Daneault | first = Audrey | last2 = Prawitt | first2 = Janne | last3 = Fabien Soulé | first3 = Véronique | last4 = Coxam | first4 = Véronique | last5 = Wittrant | first5 = Yohann | date = 2017-06-13 | title = Biological effect of hydrolyzed collagen on bone metabolism | journal = Critical Reviews in Food Science and Nutrition|volume=57 | issue = 9 | pages = 1922–1937|doi=10.1080/10408398.2015.1038377|issn=1549-7852|pmid=25976422 | url = https://zenodo.org/record/889529|url-status=live|archive-url=https://web.archive.org/web/20170913183348/https://zenodo.org/record/889529|archive-date=2017-09-13|df=}}</ref><ref>{{Cite journal | last = Jiang|first = J.X.| date = 2014 | title = Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study | url = http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR | journal = Agro FOOD Industry Hi Tech|volume=25 | pages = 19–23|via=|url-status=live|archive-url=https://web.archive.org/web/20170913183401/http://old.teknoscienze.com//articles/agro-food-industry-hi-tech-collagen-peptides-improve-knee-osteoarthritis-in-elderly-women-a.aspx#.WXCW-oSGNtR|archive-date=2017-09-13}}</ref><ref>{{Cite journal | last = Dar | first = Qurratul-Ain | last2 = Schott | first2 = Eric M. | last3 = Catheline | first3 = Sarah E. | last4 = Maynard | first4 = Robert D. | last5 = Liu | first5 = Zhaoyang | last6 = Kamal | first6 = Fadia | last7 = Farnsworth | first7 = Christopher W. | last8 = Ketz | first8 = John P. | last9 = Mooney | first9 = Robert A. | date = 2017-04-06 | title = Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis |url =http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174705 | journal = PLOS ONE|volume=12 | issue = 4| pages = e0174705|doi=10.1371/journal.pone.0174705|issn=1932-6203|pmc=5383229|pmid=28384173|url-status=live|archive-url=https://web.archive.org/web/20170913184032/http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0174705|archive-date=2017-09-13|df=|bibcode=2017PLoSO..1274705D}}</ref><ref>{{Cite journal | last = Asserin | first = Jérome | last2 = Lati | first2 = Elian | last3 = Shioya | first3 = Toshiaki | last4 = Prawitt | first4 = Janne | date = 2015-12-01 | title = The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo‐controlled clinical trials |url =http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full | journal = Journal of Cosmetic Dermatology|language=en|volume=14 | issue = 4 | pages = 291–301|doi=10.1111/jocd.12174|issn=1473-2165|url-status=live|archive-url=https://web.archive.org/web/20170910193750/http://onlinelibrary.wiley.com/doi/10.1111/jocd.12174/full|archive-date=2017-09-10}}</ref> These [[hydroxyproline]]-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.<ref>{{Cite journal | last = Ichikawa | first = Satomi | last2 = Morifuji | first2 = Masashi | last3 = Ohara | first3 = Hiroki | last4 = Matsumoto | first4 = Hitoshi | last5 = Takeuchi | first5 = Yasuo | last6 = Sato | first6 = Kenji | date = 2010-02-01 | title = Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate | url =https://dx.doi.org/10.3109/09637480903257711 | journal = International Journal of Food Sciences and Nutrition|volume=61 | issue = 1 | pages = 52–60|doi=10.3109/09637480903257711|issn=0963-7486|pmid=19961355}}</ref><ref>{{Cite journal | last = Shigemura | first = Yasutaka | last2 = Kubomura | first2 = Daiki | last3 = Sato | first3 = Yoshio | last4 = Sato | first4 = Kenji | date = 2014-09-15 | title = Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion | url =http://www.sciencedirect.com/science/article/pii/S0308814614002763 | journal = Food Chemistry|volume=159 | pages = 328–332|doi=10.1016/j.foodchem.2014.02.091}}</ref><ref>{{Cite journal | last = Watanabe-Kamiyama | first = Mari | last2 = Shimizu | first2 = Muneshige | last3 = Kamiyama | first3 = Shin | last4 = Taguchi | first4 = Yasuki | last5 = Sone | first5 = Hideyuki | last6 = Morimatsu | first6 = Fumiki | last7 = Shirakawa | first7 = Hitoshi | last8 = Furukawa | first8 = Yuji | last9 = Komai | first9 = Michio | date = 2010-01-27 | title = Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats |url =https://dx.doi.org/10.1021/jf9031487 | journal = Journal of Agricultural and Food Chemistry|volume=58 | issue = 2 | pages = 835–841|doi=10.1021/jf9031487|issn=0021-8561}}</ref>


== Potential modulators ==
== Potential modulators ==
The following are compounds that might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength.
The following are compounds that can or might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength. Compounds proven to promote connective tissue repair in vivo, or proven to reduce connective tissue-degrading [[matrix metalloproteinase]] (MMP) enzymes in vivo, are indicated by the "shown effective in vivo" column.  


{| class="wikitable"
{| class="wikitable"
!Compound
!Compound
!Type
!Type
!Shown effective in vivo
!
!
!Mechanism of action
!Mechanism of action
|-
|[[Aloe vera]]
|Polysaccharide
|
|Promotes synthesis, and inhibits destruction
|Stimulates fibroblast proliferation and collagen synthesis. Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4">{{Cite journal | last = Kudalkar | first = Mithun D. | last2 = Nayak | first2 = Aarati | last3 = Bhat | first3 = Kishore S. | last4 = Nayak | first4 = Ranganath N. | date = Jan 2014 | title = Effect of Azadirachta indica (Neem) and Aloe vera as compared to subantimicrobial dose doxycycline on matrix metalloproteinases (MMP)-2 and MMP-9: An in-vitro study | url = https://www.ncbi.nlm.nih.gov/pubmed/25364206 | journal = Ayu|volume=35 | issue = 1 | pages = 85–89|doi=10.4103/0974-8520.141947|issn=0974-8520|pmc=4213975|pmid=25364206}}</ref>
|-
|[[Pentadecapeptide BPC 157]]
|Peptide
|Yes
|Promotes synthesis
|Stimulates growth factor receptors on fibroblasts.<ref>{{Cite journal | last = Gwyer | first = Daniel | last2 = Wragg | first2 = Nicholas M. | last3 = Wilson | first3 = Samantha L. | date = Aug 2019 | title = Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing | url =https://www.ncbi.nlm.nih.gov/pubmed/30915550 | journal = Cell and Tissue Research|volume=377 | issue = 2 | pages = 153–159|doi=10.1007/s00441-019-03016-8|issn=1432-0878|pmid=30915550}}</ref><ref>{{Cite journal | last = Staresinic|first = M. | last2 = Sebecic | first2 = B. | last3 = Patrlj | first3 = L. | last4 = Jadrijevic | first4 = S. | last5 = Suknaic | first5 = S. | last6 = Perovic | first6 = D. | last7 = Aralica | first7 = G. | last8 = Zarkovic | first8 = N. | last9 = Borovic | first9 = S. | date = Nov 2003 | title = Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth | url = https://www.ncbi.nlm.nih.gov/pubmed/14554208 | journal = Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society|volume=21 | issue = 6 | pages = 976–983|doi=10.1016/S0736-0266(03)00110-4|issn=0736-0266|pmid=14554208}}</ref>
|-
|[[GABA]]
|Supplement 
|Yes
|Promotes synthesis
|GABA dramatically increases the formation of elastic fibers and up-regulates the expression of type I collagen in human dermal fibroblasts.<ref>{{Cite journal | last = Uehara | first = Eriko | last2 = Hokazono | first2 = Hideki | last3 = Hida | first3 = Mariko | last4 = Sasaki | first4 = Takako | last5 = Yoshioka | first5 = Hidekatsu | last6 = Matsuo | first6 = Noritaka | date = Jun 2017 | title = GABA promotes elastin synthesis and elastin fiber formation in normal human dermal fibroblasts (HDFs) | url = https://www.ncbi.nlm.nih.gov/pubmed/28485217 | journal = Bioscience, Biotechnology, and Biochemistry|volume=81 | issue = 6 | pages = 1198–1205|doi=10.1080/09168451.2017.1290518|issn=1347-6947|pmid=28485217}}</ref> GABA 100 mg daily is shown to increase skin skin elasticity in women.<ref>{{Cite journal | last = 絵理子|first = 上原 | last2 = 英樹 | first2 = 外薗 | date = 2016-07-15 | title = γ-アミノ酪酸の経口摂取による皮膚状態改善効果 | url = https://www.jstage.jst.go.jp/article/nskkk/63/7/63_306/_article/-char/en | journal = 日本食品科学工学会誌|language=ja|volume=63 | issue = 7 | pages = 306–311|doi=10.3136/nskkk.63.306|issn=1341-027X}}</ref>
|-
|Thymosin beta 4 (TB-500)
|Peptide
|Yes
|Promotes synthesis
|Helps repair ligaments.<ref>{{Cite journal | last = Xu|first = Bo | last2 = Yang | first2 = Mowen | last3 = Li | first3 = Zhaozhu | last4 = Zhang | first4 = Yubo | last5 = Jiang | first5 = Zhitao | last6 = Guan | first6 = Shengyang | last7 = Jiang | first7 = Dapeng | date = 2013-06-10 | title = Thymosin β4 enhances the healing of medial collateral ligament injury in rat | url = https://www.ncbi.nlm.nih.gov/pubmed/23523891 | journal = Regulatory Peptides|volume=184 | pages = 1–5|doi=10.1016/j.regpep.2013.03.026|issn=1873-1686|pmid=23523891}}</ref>
|-
|-
|Collagen peptides
|Collagen peptides
|[[Amino acid]]
|[[Amino acid]]
|
|Co-factor essential for synthesis
|Co-factor essential for synthesis
|Contains proline, lysine and other amino acids necessary for collagen synthesis.
|Contains proline, lysine and other amino acids necessary for collagen synthesis.
Line 75: Line 101:
|[[Vitamin C]]
|[[Vitamin C]]
|[[Vitamin]]
|[[Vitamin]]
|
|Co-factor essential for synthesis
|Co-factor essential for synthesis
|Catalyzes the enzymes [[procollagen-proline dioxygenase]] and lysl hydroxylase.  
|Catalyzes the enzymes [[procollagen-proline dioxygenase]] and lysl hydroxylase.  
Line 80: Line 107:
|[[Copper]]
|[[Copper]]
|[[Mineral]]
|[[Mineral]]
|
|Co-factor essential for synthesis
|Co-factor essential for synthesis
|Catalyzes the enzyme [[lysyl dioxidase]].
|Catalyzes the enzyme [[lysyl dioxidase]].
|-
|-
|[[Aloe vera]]
|[[Epigallocatechin gallate|EGCG]]
|[[Polysaccharide]]
|Supplement
|Promotes synthesis, and inhibits destruction
|Yes
|Stimulates fibroblast proliferation and collagen synthesis. Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4">{{Cite journal|last=Kudalkar|first=Mithun D.|last2=Nayak|first2=Aarati|last3=Bhat|first3=Kishore S.|last4=Nayak|first4=Ranganath N.|date=Jan 2014|title=Effect of Azadirachta indica (Neem) and Aloe vera as compared to subantimicrobial dose doxycycline on matrix metalloproteinases (MMP)-2 and MMP-9: An in-vitro study|url=https://www.ncbi.nlm.nih.gov/pubmed/25364206|journal=Ayu|volume=35|issue=1|pages=85–89|doi=10.4103/0974-8520.141947|issn=0974-8520|pmc=4213975|pmid=25364206}}</ref>
|-
|Neem
|Herb
|Inhibits destruction
|Inhibits destruction
|Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4" />
|In a human study, breast cancer patients undergoing radiotherapy ingested 400 mg oral EGCG x3 / day for several weeks. The levels of serum active MMP-9 decreased by an average of 31% at week 2 and 55% at week 8. The levels of serum MMP-2 zymogens decreased by an average of 22% at week 2 and 51% at week 8.<ref>{{Cite web | url = http://www.eurekaselect.com/76103/article | title = Anti-Cancer Activities of Tea Epigallocatechin-3-Gallate in Breast Cancer Patients under Radiotherapy | last = Zhang|first = G. | last2 = Wang | first2 = Y. | date = 2012-01-31 | website = Current Molecular Medicine|language=en|doi=10.2174/156652412798889063|access-date=2020-04-25 | last3 = Zhang | first3 = Y. | last4 = Wan | first4 = X. | last5 = Li | first5 = J. | last6 = Liu | first6 = K. | last7 = Wang | first7 = F. | last8 = Liu | first8 = Q. | last9 = Yang | first9 = C.}}</ref> EGCG doses <800mg/day have been shown to have no hepatotoxic effects according to the European Food Safety Authority.<ref>{{Cite journal | last = Younes | first = Maged | last2 = Aggett | first2 = Peter | last3 = Aguilar | first3 = Fernando | last4 = Crebelli | first4 = Riccardo | last5 = Dusemund | first5 = Birgit | last6 = Filipič | first6 = Metka | last7 = Frutos | first7 = Maria Jose | last8 = Galtier | first8 = Pierre | last9 = Gott | first9 = David | date = 2018 | title = Scientific opinion on the safety of green tea catechins |url =https://efsa.onlinelibrary.wiley.com/doi/abs/10.2903/j.efsa.2018.5239 | journal = EFSA Journal|language=en|volume=16 | issue = 4| pages = e05239|doi=10.2903/j.efsa.2018.5239|issn=1831-4732}}</ref>
|-
|[[Pentadecapeptide BPC 157]]
|[[Peptide]]
|Promotes synthesis
|Stimulates growth factor receptors on fibroblasts.<ref>{{Cite journal|last=Gwyer|first=Daniel|last2=Wragg|first2=Nicholas M.|last3=Wilson|first3=Samantha L.|date=Aug 2019|title=Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing|url=https://www.ncbi.nlm.nih.gov/pubmed/30915550|journal=Cell and Tissue Research|volume=377|issue=2|pages=153–159|doi=10.1007/s00441-019-03016-8|issn=1432-0878|pmid=30915550}}</ref><ref>{{Cite journal|last=Staresinic|first=M.|last2=Sebecic|first2=B.|last3=Patrlj|first3=L.|last4=Jadrijevic|first4=S.|last5=Suknaic|first5=S.|last6=Perovic|first6=D.|last7=Aralica|first7=G.|last8=Zarkovic|first8=N.|last9=Borovic|first9=S.|date=Nov 2003|title=Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth|url=https://www.ncbi.nlm.nih.gov/pubmed/14554208|journal=Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society|volume=21|issue=6|pages=976–983|doi=10.1016/S0736-0266(03)00110-4|issn=0736-0266|pmid=14554208}}</ref>
|-
|Thymosin beta 4 (TB-500)
|Peptide
|Promotes synthesis
|Helps repair ligaments.<ref>{{Cite journal|last=Xu|first=Bo|last2=Yang|first2=Mowen|last3=Li|first3=Zhaozhu|last4=Zhang|first4=Yubo|last5=Jiang|first5=Zhitao|last6=Guan|first6=Shengyang|last7=Jiang|first7=Dapeng|date=2013-06-10|title=Thymosin β4 enhances the healing of medial collateral ligament injury in rat|url=https://www.ncbi.nlm.nih.gov/pubmed/23523891|journal=Regulatory Peptides|volume=184|pages=1–5|doi=10.1016/j.regpep.2013.03.026|issn=1873-1686|pmid=23523891}}</ref>
|-
|-
|[[Doxycycline]]
|[[Doxycycline]]
|[[Antibiotic]]
|[[Antibiotic]]
|Yes
|Inhibits destruction
|Inhibits destruction
|Inhibits [[matrix metalloproteinase]]<nowiki/>s MMP-1, 2, 7, 8, 9, 12 and 13, and is effective at MMP inhibition at a low dose of 20 mg twice daily.<ref>{{Cite journal|last=Del Buono|first=Angelo|last2=Oliva|first2=Francesco|last3=Osti|first3=Leonardo|last4=Maffulli|first4=Nicola|date=2013-05-21|title=Metalloproteases and tendinopathy|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676164/|journal=Muscles, Ligaments and Tendons Journal|volume=3|issue=1|pages=51–57|doi=10.11138/mltj/2013.3.1.051|issn=2240-4554|pmc=3676164|pmid=23885345}}</ref>
|Inhibits matrix metalloproteinases MMP-1, 2, 7, 8, 9, 12 and 13, and is effective at MMP inhibition at a low dose of 20 mg twice daily.<ref>{{Cite journal | last = Del Buono|first = Angelo | last2 = Oliva | first2 = Francesco | last3 = Osti | first3 = Leonardo | last4 = Maffulli | first4 = Nicola | date = 2013-05-21 | title = Metalloproteases and tendinopathy | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676164/ | journal = Muscles, Ligaments and Tendons Journal|volume=3 | issue = 1 | pages = 51–57|doi=10.11138/mltj/2013.3.1.051|issn=2240-4554|pmc=3676164|pmid=23885345}}</ref> Sold as the drug Periostat, which is the only FDA approved MMP inhibitor.
|-
|-
|[[Hyaluronic acid]]
|[[Fish oil]]
|
|Supplement
|
|Yes
|
|Inhibits destruction
|Fish oil 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients.<ref>{{Cite journal | last = Shinto|first = L. | last2 = Marracci | first2 = G. | last3 = Baldauf-Wagner | first3 = S. | last4 = Strehlow | first4 = A. | last5 = Yadav | first5 = V. | last6 = Stuber | first6 = L. | last7 = Bourdette | first7 = D. | date = Feb 2009 | title = Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis |url =https://www.ncbi.nlm.nih.gov/pubmed/19171471 | journal = Prostaglandins, Leukotrienes, and Essential Fatty Acids|volume=80 | issue = 2-3 | pages = 131–136|doi=10.1016/j.plefa.2008.12.001|issn=0952-3278|pmc=2692605|pmid=19171471}}</ref>
|-
|-
|Fish oil
|Q10
|Supplement
|Supplement
|Yes
|Inhibits destruction
|Inhibits destruction
|Fish oil 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients.<ref>{{Cite journal|last=Shinto|first=L.|last2=Marracci|first2=G.|last3=Baldauf-Wagner|first3=S.|last4=Strehlow|first4=A.|last5=Yadav|first5=V.|last6=Stuber|first6=L.|last7=Bourdette|first7=D.|date=Feb 2009|title=Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis|url=https://www.ncbi.nlm.nih.gov/pubmed/19171471|journal=Prostaglandins, Leukotrienes, and Essential Fatty Acids|volume=80|issue=2-3|pages=131–136|doi=10.1016/j.plefa.2008.12.001|issn=0952-3278|pmc=2692605|pmid=19171471}}</ref>
|Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients.<ref>{{Cite journal | last = Sanoobar | first = Meisam | last2 = Eghtesadi | first2 = Shahryar | last3 = Azimi | first3 = Amirreza | last4 = Khalili | first4 = Mohammad | last5 = Khodadadi | first5 = Behnam | last6 = Jazayeri | first6 = Shima | last7 = Gohari | first7 = Mahmood Reza | last8 = Aryaeian | first8 = Nahid | date = May 2015 | title = Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial | url = https://www.ncbi.nlm.nih.gov/pubmed/24621064 | journal = Nutritional Neuroscience|volume=18 | issue = 4 | pages = 169–176|doi=10.1179/1476830513Y.0000000106|issn=1476-8305|pmid=24621064}}</ref>
|-
|-
|Q10
|[[Ecklonia cava]]
|Supplement
|Supplement
|Yes
|Inhibits destruction
|Inhibits destruction
|Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients.<ref>{{Cite journal|last=Sanoobar|first=Meisam|last2=Eghtesadi|first2=Shahryar|last3=Azimi|first3=Amirreza|last4=Khalili|first4=Mohammad|last5=Khodadadi|first5=Behnam|last6=Jazayeri|first6=Shima|last7=Gohari|first7=Mahmood Reza|last8=Aryaeian|first8=Nahid|date=May 2015|title=Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial|url=https://www.ncbi.nlm.nih.gov/pubmed/24621064|journal=Nutritional Neuroscience|volume=18|issue=4|pages=169–176|doi=10.1179/1476830513Y.0000000106|issn=1476-8305|pmid=24621064}}</ref>
|Ecklonia cava, an edible marine brown alga sold as a supplement, inhibits MMP-2 and MMP-9 and in a rat study reduced periodontitis.<ref>{{Cite journal | last = Kim|first = Seonyoung | last2 = Choi | first2 = Soo-Im | last3 = Kim | first3 = Gun-Hee | last4 = Imm | first4 = Jee-Young | date = 2019-05-22 | title = Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model | url = https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566535/ | journal = Nutrients|volume=11 | issue = 5|doi=10.3390/nu11051143|issn=2072-6643|pmc=6566535|pmid=31121899}}</ref>
|-
|-
|Ecklonia cava
|Captopril
|Marine brown alga supplement
|Drug
|Yes
|Inhibits destruction
|Inhibits destruction
|Ecklonia cava inhibits MMP-2 and MMP-9 and in a [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566535/ rat study] reduced periodontitis.<ref>{{Cite journal|last=Kim|first=Seonyoung|last2=Choi|first2=Soo-Im|last3=Kim|first3=Gun-Hee|last4=Imm|first4=Jee-Young|date=2019-05-22|title=Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566535/|journal=Nutrients|volume=11|issue=5|doi=10.3390/nu11051143|issn=2072-6643|pmc=6566535|pmid=31121899}}</ref>
|Angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease (this disease is likely caused by infection).<ref>{{Cite journal | last = Inoue | first = Nao | last2 = Takai | first2 = Shinji | last3 = Jin | first3 = Denan | last4 = Okumura | first4 = Kenichi | last5 = Okamura | first5 = Naoyuki | last6 = Kajiura | first6 = Mitsugu | last7 = Yoshikawa | first7 = Sosuke | last8 = Kawamura | first8 = Naohisa | last9 = Tamai | first9 = Hiroshi | date = Feb 2010 | title = Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease | url =https://www.ncbi.nlm.nih.gov/pubmed/19945447/ | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry|volume=411 | issue = 3-4 | pages = 267–269|doi=10.1016/j.cca.2009.11.020|issn=1873-3492|pmid=19945447}}</ref>
|-
|Losartan
|Drug
|Yes
|Inhibits destruction
|Angiotensin II receptor blocker drug losartan decreases MMP-2 and MMP-9.<ref>{{Cite journal | last = Derosa | first = Giuseppe | last2 = Maffioli | first2 = Pamela | last3 = Ferrari | first3 = Ilaria | last4 = Palumbo | first4 = Ilaria | last5 = Randazzo | first5 = Sabrina | last6 = Fogari | first6 = Elena | last7 = D'Angelo | first7 = Angela | last8 = Cicero | first8 = Arrigo F.G. | date = Jan 2011 | title = Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients |url =https://www.ncbi.nlm.nih.gov/pubmed/21107327 | journal = Hypertension Research: Official Journal of the Japanese Society of Hypertension|volume=34 | issue = 1 | pages = 145–151|doi=10.1038/hr.2010.205|issn=1348-4214|pmid=21107327}}</ref>
|-
|Neem
|Herb
|
|Inhibits destruction
|Inhibits MMP-2 and MMP-9 in vitro.<ref name=":4" />
|-
|-
|Magnesium
|Magnesium
|[[Mineral]]
|[[Mineral]]
|
|Inhibits destruction
|Inhibits destruction
|An in vitro study found magnesium reduces MMP-2.
|An in vitro study found magnesium reduces MMP-2.
Line 135: Line 167:
|Glucosamine sulfate
|Glucosamine sulfate
|Supplement
|Supplement
|
|Inhibits destruction
|Inhibits destruction
|Glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro.
|Glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro.<ref>{{Cite journal | last = Rajapakse | first = Niranjan | last2 = Mendis | first2 = Eresha | last3 = Kim | first3 = Moon-Moo | last4 = Kim | first4 = Se-Kwon | date = 2007-07-15 | title = Sulfated glucosamine inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells |url =https://www.ncbi.nlm.nih.gov/pubmed/17498959 | journal = Bioorganic & Medicinal Chemistry|volume=15 | issue = 14 | pages = 4891–4896|doi=10.1016/j.bmc.2007.04.048|issn=0968-0896|pmid=17498959}}</ref>
|-
|-
|Triphala
|Triphala
|Herbal formula
|Herbal formula
|
|Inhibits destruction
|Inhibits destruction
|Inhibits MMP-9 in vitro.<ref>{{Cite journal|last=Abraham|first=Sajith|last2=Kumar|first2=M. Senthil|last3=Sehgal|first3=P. K.|last4=Nitish|first4=S.|last5=Jayakumar|first5=N. D.|date=Apr 2005|title=Evaluation of the inhibitory effect of triphala on PMN-type matrix metalloproteinase (MMP-9)|url=https://www.ncbi.nlm.nih.gov/pubmed/15857087/|journal=Journal of Periodontology|volume=76|issue=4|pages=497–502|doi=10.1902/jop.2005.76.4.497|issn=0022-3492|pmid=15857087}}</ref>
|Inhibits MMP-9 in vitro.<ref>{{Cite journal | last = Abraham|first = Sajith | last2 = Kumar | first2 = M. Senthil | last3 = Sehgal | first3 = P.K. | last4 = Nitish | first4 = S. | last5 = Jayakumar | first5 = N.D. | date = Apr 2005 | title = Evaluation of the inhibitory effect of triphala on PMN-type matrix metalloproteinase (MMP-9) | url = https://www.ncbi.nlm.nih.gov/pubmed/15857087/ | journal = Journal of Periodontology|volume=76 | issue = 4 | pages = 497–502|doi=10.1902/jop.2005.76.4.497|issn=0022-3492|pmid=15857087}}</ref>
|-
|Vitamin K2
|Supplement
|
|
|Inhibits MMP-1 in vitro
|-
|Glucuronolactone
|Supplement
|
|Structural component
|Glucuronolactone is an important structural component of connective tissues in tendons, ligaments and cartilage. A 250 ml can of Red Bull contains 600 mg of glucuronolactone.
|-
|Hyaluronic acid
|
|
|
|
|}
|}


== See also ==
== See also ==


* [[Capillary fragility]]
* [[Ehlers-Danlos syndrome]]
* [[Ehlers-Danlos syndrome]]
* [[Mast cell activation syndrome]]
* [[Mast cell activation syndrome]]
* [[Extracellular matrix]]
* [[Extracellular matrix]]
* [[Mast cell]]
* [[Mast cell]]
* [[Osteoporosis]]
* [[Hypovitaminosis C]]
* [[Vitamin C]]


== References ==
== References ==
<references />
{{Reflist}}
[[Category:Proteins]]
[[Category:Proteins]]
[[Category:Biochemistry and cell biology]]
[[Category:Biochemistry and cell biology]]

Latest revision as of 16:34, April 3, 2023

Collagen is the main component of connective tissue and the most abundant protein in the human body. It is mostly found in fibrous tissues such as tendons, ligaments and skin.

Types[edit | edit source]

There are over 28 types of collagen found in the human body.[1] Over 90% is made of of these fives types[1]:

  • Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone)
  • Type II: cartilage (main collagenous component of cartilage)
  • Type III: reticulate (main component of reticular fibers), commonly found alongside type I.
  • Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane.
  • Type V: cell surfaces, hair, and placenta

The main collagen in ligaments is collagen type I, which comprises 70% of the dry weight of a ligament.[2] Elastin is also found at 4–9% of the dry weight in ligaments.[3]

Biology[edit | edit source]

Components[edit | edit source]

Collagen is made up primarily of the amino acids glycine and proline. The primary amino acid sequence of collagen is glycine-proline-X or glycine-X-hydroxyproline.[4] X can be any of the other 17 amino acids. Every third amino acid is glycine.[1]

Co-factors[edit | edit source]

Vitamin C is a co-factor of many of the chemical reactions involved in collagen production. Vitamin C is also a mast cell stabilizer. Vitamin C deficiency can result in impaired collagen synthesis and scurvy.[5]

Structure[edit | edit source]

Collagen is composed of three chains that wind together to form a triple helix.[1]

Biosynthesis[edit | edit source]

Collagen synthesis occurs mainly in fibroblasts, cells whose many function is the synthesis of collagen and stroma.[1] Synthesis occurs in both intracellular and extracellular spaces.[1]

Collagen-degrading factors[edit | edit source]

Pathogens[edit | edit source]

Infection can degrade collagen via direct secretion[6] of collagenases and other enzymes (in the case of bacteria) or increased host production of matrix metalloproteinases (MMPs) as part of the normal immune response (in the case of bacteria and viruses). Numerous bacteria secrete their own collagenases.[6][7] Borrelia spirochetes upregulate production of human collagenase (MMP-1) and gelatinase B (MMP-9)[8], an enzyme that can degrade both elastin and partially hydrolyzed collagen.[9] Borrelia infection has been associated with damage to collagen and elastin fibres, causing "spontaneous ruptures of tendons after slight strain, dislocation of vertebrae and an accumulation of prolapsed intervertebral discs as well as ossification of tendon insertions."[10] MMP-8 and MMP-9 are upregulated in bacterial meningitis and the latter is associated with an increased risk of blood-brain barrier breakdown and neurological sequale such as epilepsy and cognitive dysfunction.[11] Herpes simplex virus[12], HHV-6[13] and Coxsackie B[14][15] infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.[12][16][17] Coxsackie B infection induces immune cells to secrete MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12.[18][19][20]

Infection and Ehlers-Danlos Syndromes[edit | edit source]

Ehlers-Danlos Syndromes are a group connective tissue disorders caused by genetic defects in the production of collagen. Type III, hypermobile EDS (hEDS), is also thought to be genetic but as a genetic marker has not yet been identified; it is diagnosed via signs and symptoms. A 2018 case study of a patient who met the diagnostic criteria for hEDS and had a chronic Bartonella infection found their hEDS symptoms resolved with antibiotic treatment for Bartonella.[21] Mycoplasma pneumoniae has been associated with mitral valve degeneration, a complication of EDS.[22]

Fluoroquinolone antibiotics[edit | edit source]

“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”[23] A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.[24] In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.[25]

Doxycycline, by contrast, inhibits MMP production.[26][27][28][29][30][31]

Mold[edit | edit source]

Stachybotrys chartarum (black mold) release proteinases that can hydrolyze gelatin and collagen I and IV.[32] Three Mycotoxins, deoxynivalenol (DON), nivalenol (NIV) and T-2 toxin, were study in an the context of an experimental cartilage model. They were found to increase the expression of MMPs and result in the loss of aggrecan and type II collagen. Selenium partially inhibited the effects of these mycotoxins.[33]

Sex hormones[edit | edit source]

Several animal studies of collagen in muscle and the aorta have found that estrogen decreases and testosterone increases collagen and elastin.[34][35][36][37][38] A study of collagen in male cattle found that collagen synthesis increased with puberty, possibly as a result of testosterone.[39] Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).[40] An in vitro study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.[41]

In human disease[edit | edit source]

Ehlers-Danlos Syndrome[edit | edit source]

Mast cell activation syndrome[edit | edit source]

ME/CFS[edit | edit source]

Preliminary data from the UK ME/CFS biobank show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of prolyl 4-hydroxylase subunit alpha 1 (P4HA1), which encodes for procollagen-proline dioxygenase, an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of energy metabolism via downregulation of pyruvate dehydrogenase during hypoxia.[42] The data are based on self-reported diagnosis of chronic fatigue syndrome and involve a sample size that is very small for genome-wide association studies (n=1829), making confidence intervals difficult to estimate.[43]

Elevated levels of hydroxyproline, a marker of collagen breakdown, was found by Wenzhong Xiao in the Severely Ill Patient Study.[44] Robert Naviaux’s work has suggested it as a possible biomarker for female ME/CFS patients.[45] Maureen Hanson failed to find elevated hydroxyproline in her metabolomics study.[citation needed]

As a supplement[edit | edit source]

When hydrolyzed, collagen is reduced to small peptides, which can be ingested in the form of dietary supplement or functional foods and beverages with the intent to aid joint and bone health and enhance skin health.[46][47][48][49][50][51][52] These hydroxyproline-containing peptides are transported into the target tissues (e.g., skin, bones, and cartilage), where they act as building blocks for local cells and help boost the production of new collagen fibers.[53][54][55]

Potential modulators[edit | edit source]

The following are compounds that can or might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength. Compounds proven to promote connective tissue repair in vivo, or proven to reduce connective tissue-degrading matrix metalloproteinase (MMP) enzymes in vivo, are indicated by the "shown effective in vivo" column.

Compound Type Shown effective in vivo Mechanism of action
Aloe vera Polysaccharide Promotes synthesis, and inhibits destruction Stimulates fibroblast proliferation and collagen synthesis. Inhibits MMP-2 and MMP-9 in vitro.[56]
Pentadecapeptide BPC 157 Peptide Yes Promotes synthesis Stimulates growth factor receptors on fibroblasts.[57][58]
GABA Supplement  Yes Promotes synthesis GABA dramatically increases the formation of elastic fibers and up-regulates the expression of type I collagen in human dermal fibroblasts.[59] GABA 100 mg daily is shown to increase skin skin elasticity in women.[60]
Thymosin beta 4 (TB-500) Peptide Yes Promotes synthesis Helps repair ligaments.[61]
Collagen peptides Amino acid Co-factor essential for synthesis Contains proline, lysine and other amino acids necessary for collagen synthesis.
Vitamin C Vitamin Co-factor essential for synthesis Catalyzes the enzymes procollagen-proline dioxygenase and lysl hydroxylase.
Copper Mineral Co-factor essential for synthesis Catalyzes the enzyme lysyl dioxidase.
EGCG Supplement Yes Inhibits destruction In a human study, breast cancer patients undergoing radiotherapy ingested 400 mg oral EGCG x3 / day for several weeks. The levels of serum active MMP-9 decreased by an average of 31% at week 2 and 55% at week 8. The levels of serum MMP-2 zymogens decreased by an average of 22% at week 2 and 51% at week 8.[62] EGCG doses <800mg/day have been shown to have no hepatotoxic effects according to the European Food Safety Authority.[63]
Doxycycline Antibiotic Yes Inhibits destruction Inhibits matrix metalloproteinases MMP-1, 2, 7, 8, 9, 12 and 13, and is effective at MMP inhibition at a low dose of 20 mg twice daily.[64] Sold as the drug Periostat, which is the only FDA approved MMP inhibitor.
Fish oil Supplement Yes Inhibits destruction Fish oil 9.6 grams per day reduced MMP-9 secretion from immune cells by 58% after 3 months in multiple sclerosis patients.[65]
Q10 Supplement Yes Inhibits destruction Q10 at 500 mg daily reduced MMP-9 in multiple sclerosis patients.[66]
Ecklonia cava Supplement Yes Inhibits destruction Ecklonia cava, an edible marine brown alga sold as a supplement, inhibits MMP-2 and MMP-9 and in a rat study reduced periodontitis.[67]
Captopril Drug Yes Inhibits destruction Angiotensin-converting enzyme (ACE) inhibitor captopril inhibits serum MMP-9 in patients with Kawasaki disease (this disease is likely caused by infection).[68]
Losartan Drug Yes Inhibits destruction Angiotensin II receptor blocker drug losartan decreases MMP-2 and MMP-9.[69]
Neem Herb Inhibits destruction Inhibits MMP-2 and MMP-9 in vitro.[56]
Magnesium Mineral Inhibits destruction An in vitro study found magnesium reduces MMP-2.
Glucosamine sulfate Supplement Inhibits destruction Glucosamine sulfate inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells in vitro.[70]
Triphala Herbal formula Inhibits destruction Inhibits MMP-9 in vitro.[71]
Vitamin K2 Supplement Inhibits MMP-1 in vitro
Glucuronolactone Supplement Structural component Glucuronolactone is an important structural component of connective tissues in tendons, ligaments and cartilage. A 250 ml can of Red Bull contains 600 mg of glucuronolactone.
Hyaluronic acid

See also[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 1.4 1.5 Wu, Marlyn; Crane, Jonathan S. (2019). Biochemistry, Collagen Synthesis. Treasure Island (FL): StatPearls Publishing. PMID 29939531.
  2. "Ligaments". orthobullets.com. Retrieved September 16, 2019.
  3. Zitnay, Jared L.; Weiss, Jeffrey A. (December 2018). "Load Transfer, Damage and Failure in Ligaments and Tendons". Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 36 (12): 3093–3104. doi:10.1002/jor.24134. ISSN 0736-0266. PMC 6454883. PMID 30175857.
  4. Szulc, Pawel (October 2018). "Bone turnover: Biology and assessment tools". Best Practice & Research. Clinical Endocrinology & Metabolism. 32 (5): 725–738. doi:10.1016/j.beem.2018.05.003. ISSN 1878-1594. PMID 30449551.
  5. https://www.statpearls.com/ArticleLibrary/viewarticle/28798
  6. 6.0 6.1 Harrington, DJ (June 1996). "Bacterial collagenases and collagen-degrading enzymes and their potential role in human disease". Infection and Immunity. 64 (6): 1885–1891. ISSN 0019-9567. PMID 8675283.
  7. Duarte, Ana Sofia; Correia, Antonio; Esteves, Ana Cristina (2016). "Bacterial collagenases - A review". Critical Reviews in Microbiology. 42 (1): 106–126. doi:10.3109/1040841X.2014.904270. ISSN 1549-7828. PMID 24754251.
  8. Gebbia, Joseph A.; Coleman, James L.; Benach, Jorge L. (January 1, 2001). "Borrelia Spirochetes Upregulate Release and Activation of Matrix Metalloproteinase Gelatinase B (MMP-9) and Collagenase 1 (MMP-1) in Human Cells". Infection and Immunity. 69 (1): 456–462. doi:10.1128/IAI.69.1.456-462.2001. ISSN 0019-9567. PMID 11119537.
  9. Baxter, B. Timothy; MacTaggart, Jason (2009). "Pathogenesis of Aortic Aneurysms". In Hallett, John W.; Mills, Joseph L.; Earnshaw, Jonothan J.; Reekers, Jim A.; Rooke, Thom W. (eds.). Comprehensive Vascular and Endovascular Surgery (2nd ed.). Philadelphia: Mosby. pp. 465–472. doi:10.1016/b978-0-323-05726-4.00029-9. ISBN 978-0-323-05726-4.
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  30. Li, De-Quan; Lokeshwar, Balakrishna L; Solomon, Abraham; Monroy, Dagoberto; Ji, Zhonghua; Pflugfelder, Stephen C (October 1, 2001). "Regulation of MMP-9 Production by Human Corneal Epithelial Cells". Experimental Eye Research. 73 (4): 449–459. doi:10.1006/exer.2001.1054. ISSN 0014-4835.
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  42. Schneider, Martin; Harnoss, Jonathan Michael; Strowitzki, Moritz J.; Radhakrishnan, Praveen; Platzer, Lisa; Harnoss, Julian Camill; Hank, Thomas; Cai, Jun; Ulrich, Alexis (January 2015). "Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges". Hypoxia. 3: 1. doi:10.2147/HP.S60872. ISSN 2324-1128.
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