{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:00:52Z","timestamp":1791356452908,"version":"4.3.1"},"reference-count":47,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2016,3,28]],"date-time":"2016-03-28T00:00:00Z","timestamp":1459123200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Health and Medical Research Council of Australia","award":["APP512167"],"award-info":[{"award-number":["APP512167"]}]},{"name":"Arthritis Australia, and the Northern Sydney Area Grants Scheme"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p><jats:bold> To investigate the role of the heparan sulfate (HS) proteoglycan perlecan (HSPG\u20102) in regulating fibroblast growth factor (FGF) activity, bone and joint growth, and the onset and progression of posttraumatic osteoarthritis (OA)<\/jats:bold> <jats:bold>in a mouse gene\u2010knockout model.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:bold> Maturational changes were evaluated histologically in the knees of 3\u2010, 6\u2010, and 12\u2010week\u2010old wild\u2010type (WT) mice and <jats:italic>Hspg2<\/jats:italic><jats:sup>\u03943\u2212\/\u03943\u2212<\/jats:sup> mice (<jats:italic>Hspg2<\/jats:italic> lacking domain 1<\/jats:bold> <jats:bold>HS, generated by ablation of exon 3 of perlecan).<\/jats:bold> <jats:bold>Cartilage damage, subchondral bone sclerosis, osteophytosis, and synovial inflammation were scored at 4 and 8 weeks after surgical induction of OA in WT and <jats:italic>Hspg2<\/jats:italic><jats:sup>\u03943\u2212\/\u03943\u2212<\/jats:sup> mice. Changes in cartilage expression of FGF\u20102, FGF\u201018, HSPG\u20102, FGF receptor 1 (FGFR\u20101), and FGFR\u20103 were examined immunohistochemically. Femoral head cartilage from both mouse genotypes was cultured in the presence or absence of interleukin\u20101\u03b1 (IL\u20101\u03b1), FGF\u20102, and FGF\u201018, and the content and release of glycosaminoglycan (GAG) and expression of messenger RNA (mRNA) for key matrix molecules, enzymes, and inhibitors were quantified.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:bold> No effect of perlecan HS ablation on growth plate or joint development was detected. After induction of OA, <jats:italic>Hspg2<\/jats:italic><jats:sup>\u03943\u2212\/\u03943\u2212<\/jats:sup> mice had significantly reduced cartilage erosion, osteophytosis, and synovitis. OA\u2010induced loss of chondrocyte expression of FGF\u20102, FGF\u201018, and HSPG\u20102 occurred in both genotypes. Expression of FGFR\u20101 after OA induction was maintained in WT mice, while FGFR\u20103 loss after OA induction was significantly reduced in <jats:italic>Hspg2<\/jats:italic><jats:sup>\u03943\u2212\/\u03943\u2212<\/jats:sup> mice. There were no genotypic differences in GAG content or release between<\/jats:bold> <jats:bold>unstimulated control cartilage and IL\u20101\u03b1\u2013stimulated cartilage. However, IL\u20101\u03b1\u2013induced cartilage expression of <jats:italic>Mmp3<\/jats:italic> mRNA was significantly reduced in <jats:italic>Hspg2<\/jats:italic><jats:sup>\u03943\u2212\/\u03943\u2212<\/jats:sup> mice. Cartilage GAG release in either the presence or absence of IL\u20101\u03b1 was unaltered by FGF\u20102 in both genotypes. In cartilage cultures with FGF\u201018, IL\u20101\u03b1\u2013stimulated GAG loss was significantly reduced only in <jats:italic>Hspg2<\/jats:italic><jats:sup>\u03943\u2212\/\u03943\u2212<\/jats:sup> mice, and this was associated with maintained expression of <jats:italic>Fgfr3<\/jats:italic> mRNA and reduced expression of <jats:italic>Mmp2<\/jats:italic>\/<jats:italic>Mmp3<\/jats:italic> mRNA.<\/jats:bold><\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Perlecan HS has significant roles in directing the development of posttraumatic OA, potentially via the alteration of FGF\/HS\/FGFR signaling. These data suggest that the chondroprotection conferred by perlecan HS ablation could be attributed, at least in part, to the preservation of FGFR\u20103 and increased FGF signaling.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39529","type":"journal-article","created":{"date-parts":[[2015,12,4]],"date-time":"2015-12-04T19:00:07Z","timestamp":1449255607000},"page":"868-879","source":"Crossref","is-referenced-by-count":50,"title":["Ablation of Perlecan Domain 1 Heparan Sulfate Reduces Progressive Cartilage Degradation, Synovitis, and Osteophyte Size in a Preclinical Model of Posttraumatic Osteoarthritis"],"prefix":"10.1002","volume":"68","author":[{"given":"Cindy C.","family":"Shu","sequence":"first","affiliation":[{"name":"Kolling Institute, Northern Sydney Local Health District, and the University of Sydney at Royal North Shore Hospital St. Leonards New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam 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New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan S.","family":"Lord","sequence":"additional","affiliation":[{"name":"University of New South Wales Kensington New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Whitelock","sequence":"additional","affiliation":[{"name":"University of New South Wales Kensington New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher B.","family":"Little","sequence":"additional","affiliation":[{"name":"Kolling Institute, Northern Sydney Local Health District, and the University of Sydney at Royal North Shore Hospital St. Leonards New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Melrose","sequence":"additional","affiliation":[{"name":"Kolling Institute, Northern Sydney Local Health District, and the University of Sydney at Royal North Shore Hospital 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