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

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". 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.
  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.
  10. Müller, Kurt E (December 31, 2012). "Damage of Collagen and Elastic Fibres by Borrelia Burgdorferi – Known and New Clinical and Histopathological Aspects". The Open Neurology Journal. 6: 179–186. doi:10.2174/1874205X01206010179. ISSN 1874-205X. PMC 3751012. PMID 23986790.
  11. 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.
  12. 12.0 12.1 "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.
  13. "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.
  14. De Palma, Armando M.; Verbeken, Erik; Van Aelst, Ilse; Van den Steen, Philippe E.; Opdenakker, Ghislain; Neyts, Johan (December 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.
  15. "Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis". Cardiovascular Pathology. 15 (2): 63–74. March 1, 2006. doi:10.1016/j.carpath.2005.11.008. ISSN 1054-8807.
  16. 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.
  17. 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.
  18. Cheung, Caroline; Luo, Honglin; Yanagawa, Bobby; Leong, Hon Sing; Samarasekera, Dinesh; Lai, John C.K.; Suarez, Agripina; Zhang, Jingchun; McManus, Bruce M. (March 2006). "Matrix metalloproteinases and tissue inhibitors of metalloproteinases in coxsackievirus-induced myocarditis". Cardiovascular Pathology: The Official Journal of the Society for Cardiovascular Pathology. 15 (2): 63–74. doi:10.1016/j.carpath.2005.11.008. ISSN 1054-8807. PMID 16533694.
  19. Meng, Xiao-hui; Wang, Yi; Zhuang, Jian-xin; Han, Xiu-zhen; Chen, Yao; Jin, You-peng; Wang, Yu-lin; Yu, Yong-hui; Spires, James P. (August 2004). "Dynamic changes in myocardial matrix metalloproteinase activity in mice with viral myocarditis". Chinese Medical Journal. 117 (8): 1195–1199. ISSN 0366-6999. PMID 15361294.
  20. Rutschow, Susanne; Leschka, Sebastian; Westermann, Dirk; Puhl, Kerstin; Weitz, Anneke; Ladyszenskij, Leonid; Jaeger, Sebastian; Zeichhardt, Heinz; Noutsias, Michel (March 25, 2010). "Left ventricular enlargement in coxsackievirus-B3 induced chronic myocarditis--ongoing inflammation and an imbalance of the matrix degrading system". European Journal of Pharmacology. 630 (1–3): 145–151. doi:10.1016/j.ejphar.2009.12.019. ISSN 1879-0712. PMID 20035743.
  21. 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.
  22. 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.
  23. "NEJM Journal Watch: Summaries of and commentary on original medical and scientific articles from key medical journals". Retrieved June 18, 2019.
  24. Redelmeier, Donald A.; Lu, Hong; Daneman, Nick (November 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.
  25. 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.
  26. De Paiva, Cintia S.; Corrales, Rosa M.; Villarreal, Arturo L.; Farley, William J.; Li, De-Quan; Stern, Michael E.; Pflugfelder, Stephen C. (September 1, 2006). "Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye". Experimental Eye Research. 83 (3): 526–535. doi:10.1016/j.exer.2006.02.004. ISSN 0014-4835.
  27. Roach, D. M; Fitridge, R. A; Laws, P. E; Millard, S. H; Varelias, A; Cowled, P. A (March 1, 2002). "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". European Journal of Vascular and Endovascular Surgery. 23 (3): 260–269. doi:10.1053/ejvs.2002.1598. ISSN 1078-5884.
  28. 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.
  29. Choi, Dong-Hoon; Moon, Ik-Sang; Choi, Bong-Kyu; Paik, Jeong-Won; Kim, Yoon-Sik; Choi, Seong-Ho; Kim, Chong-Kwan (2004). "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". Journal of Periodontal Research. 39 (1): 20–26. doi:10.1111/j.1600-0765.2004.00696.x. ISSN 1600-0765.
  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.
  31. Brown David L.; Desai Kavita K.; Vakili Babak A.; Nouneh Chadi; Lee Hsi-Ming; Golub Lorne M. (April 1, 2004). "Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial". Arteriosclerosis, Thrombosis, and Vascular Biology. 24 (4): 733–738. doi:10.1161/01.ATV.0000121571.78696.dc.
  32. Yike, Iwona; Rand, Thomas; Dearborn, Dorr G. (July 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.
  33. 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.
  34. Fischer, G.M.; Swain, M.L. (June 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.
  35. 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.
  36. Fischer, Grace M.; Swain, Margaret L. (August 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.
  37. Fischer, G.M.; Swain, M.L. (February 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.
  38. Fischer, Grace M. (November 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.
  39. Cross, H.R.; Schanbacher, B.D.; Crouse, J.D. (January 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.
  40. Judge, M.D.; Diekman, M.A.; Lemenager, R.P.; Aberle, E.D.; Jones, S.J.; Gerrard, D.E. (November 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.
  41. Boyan, B.D.; Soskolne, W.A.; Brooks, B.P.; Ornoy, A.; Nasatzky, E.; Schwartz, Z. (April 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.
  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.
  43. "Analysis of data from 500,000 individuals in UK Biobank demonstrates an inherited component to ME/CFS". ME/CFS Research Review. June 11, 2018. Retrieved November 11, 2018.
  44. Open Medicine Foundation - OMF (November 7, 2018), Wenzhong Xiao, PhD | Results from the Severely Ill Patient Study (SIPS), retrieved July 16, 2019
  45. Naviaux, Robert K.; Naviaux, Jane C.; Kefeng, Li; Bright, A. Taylor; Alaynick, William A.; Wang, Lin; Baxter, Asha; Nathan, Neil; Anderson, Wayne; Gordon, Eric (September 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.
  46. Guillerminet, Fanny; Beaupied, Hélène; Fabien-Soulé, Véronique; Tomé, Daniel; Benhamou, Claude-Laurent; Roux, Christian; Blais, Anne (March 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.
  47. Guillerminet, F.; Fabien-Soulé, V.; Even, P.C.; Tomé, D.; Benhamou, C.-L.; Roux, C.; Blais, A. (July 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.
  48. Daneault, A. (April 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.
  49. Daneault, Audrey; Prawitt, Janne; Fabien Soulé, Véronique; Coxam, Véronique; Wittrant, Yohann (June 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 September 13, 2017.
  50. Jiang, J.X. (2014). "Collagen peptides improve knee osteoarthritis in elderly women: A 6-month randomized, double-blind, placebo-controlled study". Agro FOOD Industry Hi Tech. 25: 19–23. Archived from the original on September 13, 2017.
  51. 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. (April 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 5383229. PMID 28384173. Archived from the original on September 13, 2017.
  52. Asserin, Jérome; Lati, Elian; Shioya, Toshiaki; Prawitt, Janne (December 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 September 10, 2017.
  53. Ichikawa, Satomi; Morifuji, Masashi; Ohara, Hiroki; Matsumoto, Hitoshi; Takeuchi, Yasuo; Sato, Kenji (February 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.
  54. Shigemura, Yasutaka; Kubomura, Daiki; Sato, Yoshio; Sato, Kenji (September 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.
  55. Watanabe-Kamiyama, Mari; Shimizu, Muneshige; Kamiyama, Shin; Taguchi, Yasuki; Sone, Hideyuki; Morimatsu, Fumiki; Shirakawa, Hitoshi; Furukawa, Yuji; Komai, Michio (January 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.
  56. 56.0 56.1 Kudalkar, Mithun D.; Nayak, Aarati; Bhat, Kishore S.; Nayak, Ranganath N. (January 2014). "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". Ayu. 35 (1): 85–89. doi:10.4103/0974-8520.141947. ISSN 0974-8520. PMC 4213975. PMID 25364206.
  57. Gwyer, Daniel; Wragg, Nicholas M.; Wilson, Samantha L. (August 2019). "Gastric pentadecapeptide body protection compound BPC 157 and its role in accelerating musculoskeletal soft tissue healing". Cell and Tissue Research. 377 (2): 153–159. doi:10.1007/s00441-019-03016-8. ISSN 1432-0878. PMID 30915550.
  58. Staresinic, M.; Sebecic, B.; Patrlj, L.; Jadrijevic, S.; Suknaic, S.; Perovic, D.; Aralica, G.; Zarkovic, N.; Borovic, S. (November 2003). "Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth". Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society. 21 (6): 976–983. doi:10.1016/S0736-0266(03)00110-4. ISSN 0736-0266. PMID 14554208.
  59. Uehara, Eriko; Hokazono, Hideki; Hida, Mariko; Sasaki, Takako; Yoshioka, Hidekatsu; Matsuo, Noritaka (June 2017). "GABA promotes elastin synthesis and elastin fiber formation in normal human dermal fibroblasts (HDFs)". Bioscience, Biotechnology, and Biochemistry. 81 (6): 1198–1205. doi:10.1080/09168451.2017.1290518. ISSN 1347-6947. PMID 28485217.
  60. 絵理子, 上原; 英樹, 外薗 (July 15, 2016). "γ-アミノ酪酸の経口摂取による皮膚状態改善効果". 日本食品科学工学会誌 (in 日本語). 63 (7): 306–311. doi:10.3136/nskkk.63.306. ISSN 1341-027X.
  61. Xu, Bo; Yang, Mowen; Li, Zhaozhu; Zhang, Yubo; Jiang, Zhitao; Guan, Shengyang; Jiang, Dapeng (June 10, 2013). "Thymosin β4 enhances the healing of medial collateral ligament injury in rat". Regulatory Peptides. 184: 1–5. doi:10.1016/j.regpep.2013.03.026. ISSN 1873-1686. PMID 23523891.
  62. Zhang, G.; Wang, Y.; Zhang, Y.; Wan, X.; Li, J.; Liu, K.; Wang, F.; Liu, Q.; Yang, C. (January 31, 2012). "Anti-Cancer Activities of Tea Epigallocatechin-3-Gallate in Breast Cancer Patients under Radiotherapy". Current Molecular Medicine. doi:10.2174/156652412798889063. Retrieved April 25, 2020.
  63. Younes, Maged; Aggett, Peter; Aguilar, Fernando; Crebelli, Riccardo; Dusemund, Birgit; Filipič, Metka; Frutos, Maria Jose; Galtier, Pierre; Gott, David (2018). "Scientific opinion on the safety of green tea catechins". EFSA Journal. 16 (4): e05239. doi:10.2903/j.efsa.2018.5239. ISSN 1831-4732.
  64. Del Buono, Angelo; Oliva, Francesco; Osti, Leonardo; Maffulli, Nicola (May 21, 2013). "Metalloproteases and tendinopathy". Muscles, Ligaments and Tendons Journal. 3 (1): 51–57. doi:10.11138/mltj/2013.3.1.051. ISSN 2240-4554. PMC 3676164. PMID 23885345.
  65. Shinto, L.; Marracci, G.; Baldauf-Wagner, S.; Strehlow, A.; Yadav, V.; Stuber, L.; Bourdette, D. (February 2009). "Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 80 (2–3): 131–136. doi:10.1016/j.plefa.2008.12.001. ISSN 0952-3278. PMC 2692605. PMID 19171471.
  66. Sanoobar, Meisam; Eghtesadi, Shahryar; Azimi, Amirreza; Khalili, Mohammad; Khodadadi, Behnam; Jazayeri, Shima; Gohari, Mahmood Reza; Aryaeian, Nahid (May 2015). "Coenzyme Q10 supplementation ameliorates inflammatory markers in patients with multiple sclerosis: a double blind, placebo, controlled randomized clinical trial". Nutritional Neuroscience. 18 (4): 169–176. doi:10.1179/1476830513Y.0000000106. ISSN 1476-8305. PMID 24621064.
  67. Kim, Seonyoung; Choi, Soo-Im; Kim, Gun-Hee; Imm, Jee-Young (May 22, 2019). "Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model". Nutrients. 11 (5). doi:10.3390/nu11051143. ISSN 2072-6643. PMC 6566535. PMID 31121899.
  68. Inoue, Nao; Takai, Shinji; Jin, Denan; Okumura, Kenichi; Okamura, Naoyuki; Kajiura, Mitsugu; Yoshikawa, Sosuke; Kawamura, Naohisa; Tamai, Hiroshi (February 2010). "Effect of angiotensin-converting enzyme inhibitor on matrix metalloproteinase-9 activity in patients with Kawasaki disease". Clinica Chimica Acta; International Journal of Clinical Chemistry. 411 (3–4): 267–269. doi:10.1016/j.cca.2009.11.020. ISSN 1873-3492. PMID 19945447.
  69. Derosa, Giuseppe; Maffioli, Pamela; Ferrari, Ilaria; Palumbo, Ilaria; Randazzo, Sabrina; Fogari, Elena; D'Angelo, Angela; Cicero, Arrigo F.G. (January 2011). "Different actions of losartan and ramipril on adipose tissue activity and vascular remodeling biomarkers in hypertensive patients". Hypertension Research: Official Journal of the Japanese Society of Hypertension. 34 (1): 145–151. doi:10.1038/hr.2010.205. ISSN 1348-4214. PMID 21107327.
  70. Rajapakse, Niranjan; Mendis, Eresha; Kim, Moon-Moo; Kim, Se-Kwon (July 15, 2007). "Sulfated glucosamine inhibits MMP-2 and MMP-9 expressions in human fibrosarcoma cells". Bioorganic & Medicinal Chemistry. 15 (14): 4891–4896. doi:10.1016/j.bmc.2007.04.048. ISSN 0968-0896. PMID 17498959.
  71. Abraham, Sajith; Kumar, M. Senthil; Sehgal, P.K.; Nitish, S.; Jayakumar, N.D. (April 2005). "Evaluation of the inhibitory effect of triphala on PMN-type matrix metalloproteinase (MMP-9)". Journal of Periodontology. 76 (4): 497–502. doi:10.1902/jop.2005.76.4.497. ISSN 0022-3492. PMID 15857087.