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== Potential modulators == 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" !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.<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 |[[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]]. |- |[[Epigallocatechin gallate|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.<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> |- |[[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.<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. |- |[[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> |- |Q10 |Supplement |Yes |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]] |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.<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> |- |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).<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 |[[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.<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 |Herbal formula | |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> |- |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 | | | | |}
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