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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]

  • 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

Biosynthesis[edit | edit source]

Components[edit | edit source]

Collagen is made up primarily of glycine and proline.

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. Deficiency can result in impaired collagen synthesis and scurvy.

Collagen-degrading factors[edit | edit source]

Pathogens[edit | edit source]

Infection can degrade collagen via direct secretion[1] 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.[1][2]Borrelia spirochetes upregulate production of human collagenase (MMP-1) and gelatinase B (MMP-9)[3], an enzyme that can degrade both elastin and collagen.[4] 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.[5]Herpes simplex virus[6], HHV-6[7] and Coxsackie B[8][9] infection result in increased production of MMP-9, which is associated with Type IV and Type V collagen degradation.[6][10][11] 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.[12]Mycoplasma pneumoniae has been associated with mitral valve degeneration, a complication of EDS.[13]

Fluoroquinolone antibiotics[edit | edit source]

“Fluoroquinolones upregulate cell matrix metalloproteinases, resulting in a reduction of collagen fibrils of types I and III collagen.”[14] A longitudinal study found Fluoroquinolones increased the risk of collagen-related adverse events like tendon ruptured and detached retinas.[15] In December 2018, the FDA recommended against its use in patients with connective tissue disorders like Ehlers-Danlos Syndrome and Marfan Syndrome.[16]Doxycycline, by contrast, inhibits MMP production.

Mold[edit | edit source]

Stachybotrys chartarum (black mold) release proteinases that can hydrolyze gelatin and collagen I and IV.[17] 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.[18]

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.[19][20][21][22][23] A study of collagen in male cows found that collagen synthesis increased with puberty, possibly as a result of testosterone.[24] Another, that intramuscular collagen was higher in bulls than in steers (castrated cattle).[25] An in vitro study of rat cartilage cells found that testosterone stimulated collagen synthesis, but only in male cells.[26]

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.[27] 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.[28]

Elevated levels of hydroxyproline, a marker of collagen breakdown, was found by Wenzhong Xiao in the Severely Ill Patient Study.[29]Robert Naviaux’s work has suggested it as a possible biomarker for female ME/CFS patients.[30]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.[31][32][33][34][35][36][37] 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.[38][39][40]

See also[edit | edit source]

References[edit | edit source]

  1. 1.01.1 Harrington, D J (Jun 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. 
  2. 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. 
  3. Gebbia, Joseph A.; Coleman, James L.; Benach, Jorge L. (Jan 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. 
  4. "ScienceDirect". Retrieved Nov 9, 2018. 
  5. 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 (Apr 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 5399830Freely accessible. PMID 28431520. 
  6. 6.06.1 "Herpes-simplex virus encephalitis is characterized by an early MMP-9 increase and collagen type IV degradation". Brain Research. 1125 (1): 155–162. Dec 13, 2006. doi:10.1016/j.brainres.2006.09.093. ISSN 0006-8993. 
  7. "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. Nov 1, 2014. doi:10.1016/j.jiac.2014.07.017. ISSN 1341-321X. 
  8. De Palma, Armando M.; Verbeken, Erik; Van Aelst, Ilse; Van den Steen, Philippe E.; Opdenakker, Ghislain; Neyts, Johan (Dec 5, 2008). "Increased gelatinase B/matrix metalloproteinase 9 (MMP-9) activity in a murine model of acute coxsackievirus B4-induced pancreatitis". Virology. 382 (1): 20–27. doi:10.1016/j.virol.2008.08.046. ISSN 1096-0341. PMID 18929380. 
  9. "Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis". Cardiovascular Pathology. 15 (2): 63–74. Mar 1, 2006. doi:10.1016/j.carpath.2005.11.008. ISSN 1054-8807. 
  10. 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. 
  11. Van den Steen, Philippe E.; Dubois, Bénédicte; Nelissen, Inge; Rudd, Pauline M.; Dwek, Raymond A.; Opdenakker, Ghislain (Jan 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. 
  12. Mozayeni, Bobak Robert; Maggi, Ricardo Guillermo; Bradley, Julie Meredith; Breitschwerdt, Edward Bealmear (Apr 2018). "Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias". Medicine. 97 (17): e0465. doi:10.1097/MD.0000000000010465. ISSN 0025-7974. 
  13. 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 (Apr 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 5399830Freely accessible. PMID 28431520. 
  14. "NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals". Retrieved Jun 18, 2019. 
  15. Redelmeier, Donald A.; Lu, Hong; Daneman, Nick (Nov 1, 2015). "Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study". BMJ Open. 5 (11): e010077. doi:10.1136/bmjopen-2015-010077. ISSN 2044-6055. PMID 26582407. 
  16. Research, Center for Drug Evaluation and (Apr 15, 2019). "FDA warns about increased risk of ruptures or tears in the aorta blood vessel with fluoroquinolone antibiotics in certain patients". FDA. 
  17. Yike, Iwona; Rand, Thomas; Dearborn, Dorr G. (Jul 3, 2007). "The role of fungal proteinases in pathophysiology of Stachybotrys chartarum". Mycopathologia. 164 (4): 171. doi:10.1007/s11046-007-9037-4. ISSN 1573-0832. 
  18. Caterson, Bruce; Li, Jin; Wang, Jiali; Luo, Mingxiu; Liu, Jiayuan; Zhang, Zengtie; Fu, Qiang; Chen, Jinghong; Li, Siyuan (2012). "The Effects of Mycotoxins and Selenium Deficiency on Tissue-Engineered Cartilage". Cells Tissues Organs. 196 (3): 241–250. doi:10.1159/000335046. ISSN 1422-6405. PMID 22538829. 
  19. Fischer, G. M.; Swain, M. L. (Jun 1, 1977). "Effect of sex hormones on blood pressure and vascular connective tissue in castrated and noncastrated male rats". American Journal of Physiology-Heart and Circulatory Physiology. 232 (6): H617–H621. doi:10.1152/ajpheart.1977.232.6.H617. ISSN 0363-6135. 
  20. Cembrano, JosÉ; Lillo, Manuel; Val, JosÉ; Mardones, Jorge (May 1, 1960). "Influence of Sex Difference and Hormones on Elastine and Collagen in the Aorta of Chickens". Circulation Research. 8 (3): 527–529. ISSN 0009-7330. PMID 13808759. 
  21. Fischer, Grace M.; Swain, Margaret L. (Aug 1, 1980). "Influence of contraceptive and other sex steroids on aortic collagen and elastin". Experimental and Molecular Pathology. 33 (1): 15–24. doi:10.1016/0014-4800(80)90003-9. ISSN 0014-4800. 
  22. Fischer, G. M.; Swain, M. L. (Feb 1, 1985). "Effects of estradiol and progesterone on the increased synthesis of collagen in atherosclerotic rabbit aortas". Atherosclerosis. 54 (2): 177–185. doi:10.1016/0021-9150(85)90177-7. ISSN 0021-9150. 
  23. Fischer, Grace M. (Nov 1, 1972). "In Vivo EflEects of Estradiol on Collagen and Elastin Dynamics in Rat Aorta". Endocrinology. 91 (5): 1227–1232. doi:10.1210/endo-91-5-1227. ISSN 0013-7227. 
  24. Cross, H. R.; Schanbacher, B. D.; Crouse, J. D. (Jan 1, 1984). "Sex, age and breed related changes in bovine testosterone and intramuscular collagen". Meat Science. 10 (3): 187–195. doi:10.1016/0309-1740(84)90021-4. ISSN 0309-1740. 
  25. Judge, M. D.; Diekman, M. A.; Lemenager, R. P.; Aberle, E. D.; Jones, S. J.; Gerrard, D. E. (Nov 1, 1987). "Collagen Stability, Testosterone Secretion and Meat Tenderness in Growing Bulls and Steers". Journal of Animal Science. 65 (5): 1236–1242. doi:10.2527/jas1987.6551236x. ISSN 0021-8812. 
  26. Boyan, B. D.; Soskolne, W. A.; Brooks, B. P.; Ornoy, A.; Nasatzky, E.; Schwartz, Z. (Apr 1, 1994). "Gender-specific, maturation-dependent effects of testosterone on chondrocytes in culture". Endocrinology. 134 (4): 1640–1647. doi:10.1210/endo.134.4.8137726. ISSN 0013-7227. 
  27. Schneider, Martin; Harnoss, Jonathan Michael; Strowitzki, Moritz J.; Radhakrishnan, Praveen; Platzer, Lisa; Harnoss, Julian Camill; Hank, Thomas; Cai, Jun; Ulrich, Alexis (Jan 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. 
  28. "Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS". ME/CFS Research Review. Jun 11, 2018. Retrieved Nov 11, 2018. 
  29. Open Medicine Foundation - OMF (Nov 7, 2018), Wenzhong Xiao, PhD | Results from the Severely Ill Patient Study (SIPS), retrieved Jul 16, 2019 
  30. Gordon, Eric; Anderson, Wayne; Nathan, Neil; Baxter, Asha; Wang, Lin; Alaynick, William A.; Bright, A. Taylor; Li, Kefeng; Naviaux, Jane C. (Sep 13, 2016). "Metabolic features of chronic fatigue syndrome". Proceedings of the National Academy of Sciences. 113 (37): E5472–E5480. doi:10.1073/pnas.1607571113. ISSN 0027-8424. PMID 27573827. 
  31. Guillerminet, Fanny; Beaupied, Hélène; Fabien-Soulé, Véronique; Tomé, Daniel; Benhamou, Claude-Laurent; Roux, Christian; Blais, Anne (Mar 1, 2010). "Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: An in vitro and in vivo study". Bone. 46 (3): 827–834. doi:10.1016/j.bone.2009.10.035. ISSN 8756-3282. 
  32. Guillerminet, F.; Fabien-Soulé, V.; Even, P. C.; Tomé, D.; Benhamou, C.-L.; Roux, C.; Blais, A. (Jul 1, 2012). "Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice". Osteoporosis International. 23 (7): 1909–1919. doi:10.1007/s00198-011-1788-6. ISSN 0937-941X. 
  33. Daneault, A. (Apr 1, 2014). "Hydrolyzed collagen contributes to osteoblast differentiation in vitro and subsequent bone health in vivo". Osteoarthritis and Cartilage. 22: S131. doi:10.1016/j.joca.2014.02.240. ISSN 1063-4584. 
  34. Daneault, Audrey; Prawitt, Janne; Fabien Soulé, Véronique; Coxam, Véronique; Wittrant, Yohann (Jun 13, 2017). "Biological effect of hydrolyzed collagen on bone metabolism". Critical Reviews in Food Science and Nutrition. 57 (9): 1922–1937. doi:10.1080/10408398.2015.1038377. ISSN 1549-7852. PMID 25976422. Archived from the original on Sep 13, 2017. 
  35. Jiang, J.X. (2014). "Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study". Agro FOOD Indusrty Hi Tech. 25: 19–23. Archived from the original on Sep 13, 2017. 
  36. Dar, Qurratul-Ain; Schott, Eric M.; Catheline, Sarah E.; Maynard, Robert D.; Liu, Zhaoyang; Kamal, Fadia; Farnsworth, Christopher W.; Ketz, John P.; Mooney, Robert A. (Apr 6, 2017). "Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis". PLOS ONE. 12 (4): e0174705. Bibcode:2017PLoSO..1274705D. doi:10.1371/journal.pone.0174705. ISSN 1932-6203. PMC 5383229Freely accessible. PMID 28384173. Archived from the original on Sep 13, 2017. 
  37. Asserin, Jérome; Lati, Elian; Shioya, Toshiaki; Prawitt, Janne (Dec 1, 2015). "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". Journal of Cosmetic Dermatology. 14 (4): 291–301. doi:10.1111/jocd.12174. ISSN 1473-2165. Archived from the original on Sep 10, 2017. 
  38. Ichikawa, Satomi; Morifuji, Masashi; Ohara, Hiroki; Matsumoto, Hitoshi; Takeuchi, Yasuo; Sato, Kenji (Feb 1, 2010). "Hydroxyproline-containing dipeptides and tripeptides quantified at high concentration in human blood after oral administration of gelatin hydrolysate". International Journal of Food Sciences and Nutrition. 61 (1): 52–60. doi:10.3109/09637480903257711. ISSN 0963-7486. PMID 19961355. 
  39. Shigemura, Yasutaka; Kubomura, Daiki; Sato, Yoshio; Sato, Kenji (Sep 15, 2014). "Dose-dependent changes in the levels of free and peptide forms of hydroxyproline in human plasma after collagen hydrolysate ingestion". Food Chemistry. 159: 328–332. doi:10.1016/j.foodchem.2014.02.091. 
  40. Watanabe-Kamiyama, Mari; Shimizu, Muneshige; Kamiyama, Shin; Taguchi, Yasuki; Sone, Hideyuki; Morimatsu, Fumiki; Shirakawa, Hitoshi; Furukawa, Yuji; Komai, Michio (Jan 27, 2010). "Absorption and Effectiveness of Orally Administered Low Molecular Weight Collagen Hydrolysate in Rats". Journal of Agricultural and Food Chemistry. 58 (2): 835–841. doi:10.1021/jf9031487. ISSN 0021-8561. 

Myalgic encephalomyelitis or chronic fatigue syndrome

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From MEpedia, a crowd-sourced encyclopedia of ME and CFS science and history