Collagen

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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

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.[2] 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.[citation needed]

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[3] 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.[3][4] Borrelia spirochetes upregulate production of human collagenase (MMP-1) and gelatinase B (MMP-9)[5], an enzyme that can degrade both elastin and collagen.[6] 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 impairment.[7] Herpes simplex virus[8], HHV-6[9] and Coxsackie B[10][11] infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.[8][12][13] Coxsackie B has also been associated with increased production of other MMPs.

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

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.[14] Mycoplasma pneumoniae has been associated with mitral valve degeneration, a complication of EDS.[15]

Fluoroquinolone antibiotics[edit | edit source]

“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”[16] A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.[17] In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.[18]

Doxycycline, by contrast, inhibits MMP production.[19][20][21][22][23][24]

Mold[edit | edit source]

Stachybotrys chartarum (black mold) release proteinases that can hydrolyze gelatin and collagen I and IV.[25] 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.[26]

Sex hormones[edit | edit source]

Several animal studies of collagen in muscle and the aorta have found that estrogen decreases and testosterone collagen and elastin.[27][28][29][30][31] A study of collagen in male cows found that collagen synthesis increased with puberty, possibly as a result of testosterone.[32] Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).[33] An in vitro study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.[34]

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 that also plays a role in the regulation of energy metabolism via downregulation of pyruvate dehydrogenase during hypoxia.[35] 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.[36]

Elevated levels of hydroxyproline, a marker of collagen breakdown, was found by Wenzhong Xiao in the Severely Ill Patient Study.[37] Robert Naviaux’s work has suggested it as a possible biomarker for female ME/CFS patients.[38] 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.[39][40][41][42][43][44][45] 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.[46][47][48]

Potential treatments[edit | edit source]

The following are compounds that might increase collagen synthesis, inhibit collagen destruction, or improve collagen strength.

Compound Type Mechanism of action
Collagen peptides Essential for synthesis
Vitamin C Co-factor Essential for synthesis Catalyzes the enzymes procollagen-proline dioxygenase and lysl hydroxylase
Aloe vera Polysaccharide Promotes synthesis Stimulates fibroblast proliferation and collagen synthesis
Pentadecapeptide BPC 157 Peptide
Doxycyline Antibiotic Inhibits destruction Inhibits matrix metalloproteinases
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. Cite journal requires |journal= (help)
  2. Szulc, Pawel (10 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. Check date values in: |date= (help)
  3. 3.0 3.1 Harrington, D J (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.
  4. 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.
  5. 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.
  6. "ScienceDirect". www.sciencedirect.com. Retrieved November 9, 2018.
  7. Tiveron, Marcos Gradim; Pomerantzeff, Pablo Maria Alberto; de Lourdes Higuchi, Maria; Reis, Marcia Martins; de Jesus Pereira, Jaqueline; Kawakami, Joyce Tieko; Ikegami, Renata Nishiyama; de Almeida Brandao, Carlos Manuel; Jatene, Fabio Biscegli (April 21, 2017). "Infectious agents is a risk factor for myxomatous mitral valve degeneration: A case control study". BMC infectious diseases. 17 (1): 297. doi:10.1186/s12879-017-2387-8. ISSN 1471-2334. PMC 5399830. PMID 28431520.
  8. 8.0 8.1 "Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation". Brain Research. 1125 (1): 155–162. December 13, 2006. doi:10.1016/j.brainres.2006.09.093. ISSN 0006-8993.
  9. "Serum levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases-1 in human herpesvirus-6–infected infants with or without febrile seizures". Journal of Infection and Chemotherapy. 20 (11): 716–721. November 1, 2014. doi:10.1016/j.jiac.2014.07.017. ISSN 1341-321X.
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  12. Zeng, Z. S.; Cohen, A. M.; Guillem, J. G. (May 1999). "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". Carcinogenesis. 20 (5): 749–755. ISSN 0143-3334. PMID 10334190.
  13. Van den Steen, Philippe E.; Dubois, Bénédicte; Nelissen, Inge; Rudd, Pauline M.; Dwek, Raymond A.; Opdenakker, Ghislain (January 2002). "Biochemistry and Molecular Biology of Gelatinase B or Matrix Metalloproteinase-9 (MMP-9)". Critical Reviews in Biochemistry and Molecular Biology. 37 (6): 375–536. doi:10.1080/10409230290771546. ISSN 1040-9238.
  14. Mozayeni, Bobak Robert; Maggi, Ricardo Guillermo; Bradley, Julie Meredith; Breitschwerdt, Edward Bealmear (April 2018). "Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias". Medicine. 97 (17): e0465. doi:10.1097/MD.0000000000010465. ISSN 0025-7974.
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  18. Research, Center for Drug Evaluation and (April 15, 2019). "FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients". FDA.
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  21. Niedzwiecki, A.; Rath, M.; Kalinovsky, T.; Monterrey, J. C.; Roomi, M. W. (March 1, 2010). "In vitro modulation of MMP-2 and MMP-9 in human cervical and ovarian cancer cell lines by cytokines, inducers and inhibitors". Oncology Reports. 23 (3): 605–614. doi:10.3892/or_00000675. ISSN 1021-335X.
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