{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T08:11:57Z","timestamp":1791101517742,"version":"4.1.0"},"reference-count":22,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2012,3,3]],"date-time":"2012-03-03T00:00:00Z","timestamp":1330732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Oral Pathology Medicine"],"published-print":{"date-parts":[[2012,7]]},"abstract":"<jats:p><jats:italic>J Oral Pathol Med<\/jats:italic> (2012) <jats:bold>41<\/jats:bold>: 454\u2013462<\/jats:p><jats:p>Oral submucous fibrosis (OSMF) is associated with paan chewing, altered collagen metabolism, inflammation and the upregulation of numerous cytokines. OSMF fibroblasts accumulate senescent cells at an increased rate because of increased reactive oxygen species production and DNA double\u2010strand breaks (DDBs), generated intrinsically by damaged mitochondria. This results in a reduced replicative lifespan. However, it is still unclear which other changes are intrinsic to the fibroblasts and associated with OSMF rather than the paan chewing habit or the OSMF environment. Both the oral epithelium and the mesenchyme have elevated levels of TGF\u2010\u03b2<jats:sub>1<\/jats:sub> in OSMF <jats:italic>in vivo<\/jats:italic>. However, in cultured fibroblasts, secreted levels of TGF\u2010\u03b2<jats:sub>1,<\/jats:sub> other cytokines and the matrix metalloproteinases 1 and 2 showed no association with OSMF. In contrast, the tissue inhibitors of metalloproteinases, TIMP\u20101 and TIMP\u20102, were increased in 10\/11 OSMF fibroblast cultures relative to normal and non\u2010diseased paan user controls. OSMF fibroblast collagen levels were normal. TIMP levels correlated with replicative lifespan of the cultures but not with the presence of senescent cells, as senescent cell depletion in OSMF fibroblast cultures did not result in a reduction in either TIMP\u20101 or TIMP\u20102. However, the introduction of unrepairable DDBs into normal oral fibroblasts by ionizing radiation increased TIMP\u20101 and TIMP\u20102 secretion by two\u2010fold and seven\u2010fold, respectively, within 5\u2003days, replicating early senescence and the elevation seen in OSMF cultures. Therefore, increased fibroblast TIMP\u20101\/2 levels could be early disease\u2010specific markers of OSMF onset, DDBs and ageing and may have clinical significance, as OSMF can be reversed in its early stages.<\/jats:p>","DOI":"10.1111\/j.1600-0714.2012.01129.x","type":"journal-article","created":{"date-parts":[[2012,3,5]],"date-time":"2012-03-05T17:10:37Z","timestamp":1330967437000},"page":"454-462","source":"Crossref","is-referenced-by-count":35,"title":["Increased secretion of tissue inhibitors of metalloproteinases 1 and 2 (TIMPs \u20101 and \u20102) in fibroblasts are early indictors of oral sub\u2010mucous fibrosis and ageing"],"prefix":"10.1111","volume":"41","author":[{"given":"Gayani N.","family":"Pitiyage","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kue P.","family":"Lim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilios","family":"Gemenitzidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muy\u2010Teck","family":"Teh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Waseem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen S.","family":"Prime","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanninayake M.","family":"Tilakaratne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farida","family":"Fortune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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