{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T22:43:05Z","timestamp":1790808185719,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["Grant Number 26461654"],"award-info":[{"award-number":["Grant Number 26461654"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Several studies have demonstrated that the secreted glycoprotein and integrin ligand milk fat globule\u2013associated protein with epidermal growth factor\u2013 and factor VIII\u2013like domains (MFG\u2010E8) negatively regulates fibrosis in the liver, lungs, and respiratory tract. However, the mechanisms and roles of MFG\u2010E8 in skin fibrosis in systemic sclerosis (SSc) have not been characterized. We undertook this study to elucidate the role of MFG\u2010E8 in skin fibrosis in SSc.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We assessed expression of MFG\u2010E8 in the skin and serum in SSc patients. We examined the effect of recombinant MFG\u2010E8 (rMFG\u2010E8) on latent transforming growth factor \u03b2 (TGF\u03b2)\u2013induced gene\/protein expression in SSc fibroblasts. We examined the effects of deficiency or administration of MFG\u2010E8 on fibrosis mouse models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated that MFG\u2010E8 expression around dermal blood vessels and the serum MFG\u2010E8 level in SSc patients (n = 7 and n = 44, respectively) were lower than those in healthy individuals (n = 6 and n = 28, respectively). Treatment with rMFG\u2010E8 significantly inhibited latent TGF\u03b2\u2013induced expression of type I collagen, \u03b1\u2010smooth muscle actin, and CCN2 in SSc fibroblasts (n = 3\u20138), which suggested that MFG\u2010E8 inhibited activation of latent TGF\u03b2 as well as TGF\u03b2 signaling via binding to \u03b1v integrin. In a mouse model of bleomycin\u2010induced fibrosis (n = 5\u20138) and in a TSK mouse model (a genetic model of SSc) (n = 5\u201310), deficient expression of MFG\u2010E8 significantly enhanced both pulmonary and skin fibrosis, and administration of rMFG\u2010E8 significantly inhibited bleomycin\u2010induced dermal fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results suggest that vasculopathy\u2010induced dysfunction of pericytes and endothelial cells, the main cells secreting MFG\u2010E8, may be associated with the decreased expression of MFG\u2010E8 in SSc and that the deficient inhibitory regulation of latent TGF\u03b2\u2013induced skin fibrosis by MFG\u2010E8 may be involved in the pathogenesis of SSc and may be a therapeutic target for fibrosis in SSc patients.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40701","type":"journal-article","created":{"date-parts":[[2018,9,3]],"date-time":"2018-09-03T07:19:27Z","timestamp":1535959167000},"page":"302-314","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Suppressive Regulation by MFG\u2010E8 of Latent Transforming Growth Factor \u03b2\u2013Induced Fibrosis via Binding to \u03b1v Integrin: Significance in the Pathogenesis of Fibrosis in Systemic Sclerosis"],"prefix":"10.1002","volume":"71","author":[{"given":"Chisako","family":"Fujiwara","sequence":"first","affiliation":[{"name":"Gunma University Graduate School of Medicine  Maebashi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Uehara","sequence":"additional","affiliation":[{"name":"Gunma University Graduate School of Medicine  Maebashi 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