{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:46:16Z","timestamp":1791326776121,"version":"4.3.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2008,8,1]],"date-time":"2008-08-01T00:00:00Z","timestamp":1217548800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Osteoporosis is a major cause of morbidity and decreased quality of life in patients with chronic cholestatic liver disease. It is established that this osteoporosis results from decreased bone formation, but the mechanisms for the interaction between liver and bone remain elusive. The aim of this study was to test the hypothesis that an increase in the production of cellular fibronectins during liver disease may result in decreased osteoblast-mediated mineralization and thus explain the decrease in bone formation. We performed a prospective cross-sectional study in patients with primary biliary cirrhosis and matched controls, followed by experiments on human and mouse osteoblasts in culture and injections in mice in vivo. In patients with primary biliary cirrhosis, the oncofetal domain of fibronectin correlated significantly with the decrease in osteocalcin, a marker of bone formation (r = \u22120.57, p &amp;lt; 0.05). In vitro, amniotic fluid fibronectin (aFN) containing mainly the oncofetal domain and EIIIA domain resulted in decreased osteoblast-mediated mineralization in human osteoblasts (69% decrease at 100 \u03bcg\/ml; p &amp;lt; 0.01) and mouse osteoblasts (71% decrease; p &amp;lt; 0.05). Removing the EIIIA domain from aFN similarly suppressed mineralization by osteoblasts (78% decrease; p &amp;lt; 0.05). Injection of labeled aFN in mice showed that it infiltrates the bone, and its administration over 10 days resulted in decreased trabecular BMD (17% drop; p &amp;lt; 0.05), mineralizing surface (30% drop; p &amp;lt; 0.005), and number of osteoblasts (45% drop; p &amp;lt; 0.05). Increased production of a fibronectin isoform containing the oncofetal domain and its release in the circulation in patients with primary biliary cirrhosis is at least partially responsible for the decrease in bone formation seen in these patients. This establishes that a molecule that has thus far been viewed as an extracellular matrix protein exerts hormone-like actions.<\/jats:p>","DOI":"10.1359\/jbmr.080313","type":"journal-article","created":{"date-parts":[[2008,3,18]],"date-time":"2008-03-18T14:40:08Z","timestamp":1205851208000},"page":"1278-1286","source":"Crossref","is-referenced-by-count":60,"title":["Isoform of Fibronectin Mediates Bone Loss in Patients With Primary Biliary Cirrhosis by Suppressing Bone Formation"],"prefix":"10.1093","volume":"23","author":[{"given":"Nina","family":"Kawelke","sequence":"first","affiliation":[{"name":"Institute for Immunology, University of Heidelberg, Heidelberg, Germany"},{"name":"Max-Planck Institute for Biochemistry, Martinsried, Germany"},{"name":"These authors contributed equally to this work"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Bentmann","sequence":"additional","affiliation":[{"name":"Institute for Immunology, University of Heidelberg, Heidelberg, Germany"},{"name":"Max-Planck Institute for Biochemistry, Martinsried, Germany"},{"name":"These authors contributed equally to this work"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norman","family":"Hackl","sequence":"additional","affiliation":[{"name":"Max-Planck Institute for Biochemistry, Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Dieter","family":"Hager","sequence":"additional","affiliation":[{"name":"Institute for Human Genetics, University of Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Feick","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University of Heidelberg at Mannheim, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Geursen","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University of Heidelberg at Mannheim, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred V","family":"Singer","sequence":"additional","affiliation":[{"name":"Department of Medicine II, University of Heidelberg at Mannheim, Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inaam A","family":"Nakchbandi","sequence":"additional","affiliation":[{"name":"Institute for Immunology, University of Heidelberg, Heidelberg, Germany"},{"name":"Max-Planck Institute for Biochemistry, Martinsried, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,12,4]]},"reference":[{"key":"2024020319511566800_bib1","first-page":"S26","article-title":"Bone disease in primary biliary cirrhosis: A large scale prevalence study","volume":"3","author":"Camisasca","year":"1991","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"2024020319511566800_bib2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1136\/gut.31.1.82","article-title":"Osteoporosis and skeletal fractures in chronic liver disease","volume":"31","author":"Diamond","year":"1990","journal-title":"Gut"},{"key":"2024020319511566800_bib3","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/0016-5085(95)90033-0","article-title":"Bone disease in cholestatic liver disease","volume":"108","author":"Hay","year":"1995","journal-title":"Gastroenterology"},{"key":"2024020319511566800_bib4","first-page":"783","article-title":"Osteoporosis in chronic cholestatic liver disease","volume":"57","author":"Stellon","year":"1985","journal-title":"Q J Med"},{"key":"2024020319511566800_bib5","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/8756-3282(86)90015-3","article-title":"Lack of osteomalacia in chronic cholestatic liver disease","volume":"7","author":"Stellon","year":"1986","journal-title":"Bone"},{"key":"2024020319511566800_bib6","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1210\/jcem-69-6-1234","article-title":"Serum vitamin D metabolites are not responsible for low turnover osteoporosis in chronic liver disease","volume":"69","author":"Diamond","year":"1989","journal-title":"J Clin Endocrinol Metab"},{"key":"2024020319511566800_bib7","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1172\/JCI117959","article-title":"Role of hyperbilirubinemia in the impairment of osteoblast proliferation associated with cholestatic jaundice","volume":"95","author":"Janes","year":"1995","journal-title":"J Clin Invest"},{"key":"2024020319511566800_bib8","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/0016-5085(89)90783-X","article-title":"Hepatic osteodystrophy. 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