{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:27:38Z","timestamp":1791854858064,"version":"4.3.4"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["asbmr.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["JBMR Plus"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Legg\u2010Calv\u00e9\u2010Perthes disease (LCPD) is a childhood ischemic osteonecrosis (ON) of the femoral head associated with the elevation of proinflammatory cytokine interleukin\u20106 (IL\u20106) in the synovial fluid. Currently, there is no effective medical therapy for patients with LCPD. In animal models of ischemic ON, articular chondrocytes produce IL\u20106 in response to ischemic ON induction and IL\u20106 receptor blockade improves bone healing. High\u2010mobility group box 1 (HMGB1) is a damage\u2010associated molecular pattern released from dying cells. In addition, extracellular HMGB1 protein is a well\u2010known proinflammatory cytokine elevated in the synovial fluid of patients with rheumatoid arthritis and osteoarthritis. The purpose of this study was to investigate IL\u20106\u2013related proinflammatory cytokines, including HMGB1, in the synovial fluid of patients with LCPD. Our working hypothesis was that HMGB1, produced by articular chondrocytes following ischemic ON, plays an important role in IL\u20106 upregulation. Here, HMGB1 protein levels were significantly higher in the synovial fluid of patients with LCPD by threefold compared with controls (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05), and were highly correlated with IL\u20106 levels (Pearson correlation coefficient 0.94,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001,\n                    <jats:italic>R<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    = 0.87). In the mouse model of ischemic ON, both HMGB1 gene expression and protein levels were elevated in the articular cartilage. In vitro studies revealed a significant elevation of HMGB1 and IL\u20106 proteins in the supernatants of human chondrocytes exposed to hypoxic and oxidative stresses. Overexpressed HMGB1 protein in the supernatants of chondrocytes synergistically increased IL\u20106 protein. Silencing\n                    <jats:italic>HMGB1<\/jats:italic>\n                    RNA in human chondrocytes significantly repressed inteleukin\u20101\u03b2 (IL\u20101\u03b2) gene expression, but not IL\u20106. Further, both IL\u20101\u03b2 and tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) protein levels in the synovial fluid of patients with LCPD were significantly correlated with IL\u20106 protein levels. Taken together, these results suggest that proinflammatory cytokines, HMGB1, tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), and IL\u20101\u03b2, are significantly involved with IL\u20106 in the pathogenesis of LCPD. This study is clinically relevant because the availability of multiple therapeutic targets may improve the development of therapeutic strategy for LCPD. \u00a9 2020 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10429","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T12:01:16Z","timestamp":1604404876000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Elevation of Proinflammatory Cytokine\n                    <scp>HMGB1<\/scp>\n                    in the Synovial Fluid of Patients With\n                    <scp>Legg\u2010Calv\u00e9\u2010Perthes<\/scp>\n                    Disease and Correlation With\n                    <scp>IL<\/scp>\n                    \u20106"],"prefix":"10.1093","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3637-2282","authenticated-orcid":false,"given":"Nobuhiro","family":"Kamiya","sequence":"first","affiliation":[{"name":"Center for Excellence in Hip Scottish Rite for Children  Dallas TX USA"},{"name":"Department of Orthopedic Surgery University of Texas Southwestern Medical Center  Dallas TX USA"},{"name":"Faculty of Budo and Sport Studies Tenri University  Nara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0330-4777","authenticated-orcid":false,"given":"Harry KW","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Excellence in Hip Scottish Rite for Children  Dallas TX USA"},{"name":"Department of Orthopedic Surgery University of Texas Southwestern Medical Center  Dallas TX USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196611032751804"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ocl.2011.03.002"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-198466060-00006"},{"key":"e_1_2_8_5_1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/00003086-198007000-00019","article-title":"Methods of measuring in Legg\u2010Calve\u2010Perthes disease with special regard to the prognosis","volume":"150","author":"Mose K","year":"1980","journal-title":"Clin Orthop Relat Res."},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2106\/00004623-198163070-00006"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1302\/0301-620X.64B3.6807991"},{"key":"e_1_2_8_8_1","first-page":"5","article-title":"Coxa plana: a histo\u2010pathologic 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