{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T20:03:23Z","timestamp":1792440203535,"version":"4.5.0"},"reference-count":33,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2015,10,28]],"date-time":"2015-10-28T00:00:00Z","timestamp":1445990400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Dutch Arthritis Foundation","award":["LLP14"],"award-info":[{"award-number":["LLP14"]}]},{"name":"Dutch Arthritis Foundation","award":["13-2-201"],"award-info":[{"award-number":["13-2-201"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Osteoarthritis (OA) development involves a shift of the articular chondrocyte phenotype toward hypertrophic differentiation via still poorly characterized mechanisms. The purpose of this study was to test our hypothesis that the function of BAPX\u20101\/NKX\u20103.2 is impaired in OA chondrocytes and leads directly to loss of hypertrophic protection of the articular chondrocyte, which is central in the changing chondrocyte phenotype that drives OA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human articular chondrocytes (HACs; from healthy and OA donors) and SW\u20101353 chondrocytic cells were exposed to bone morphogenetic protein 7 (BMP\u20107), interleukin\u20101\u03b2 (IL\u20101\u03b2), tumor necrosis factor, or OA synovial fluid (SF; 20% [volume\/volume]). Loss\u2010of\u2010function and gain\u2010of\u2010function experiments for BAPX\u20101\/NKX\u20103.2 were performed. Mouse experimental models of OA were used, and (immuno)histochemistry of tissue sections was performed. Gene and protein expression of BAPX\u20101\/NKX\u20103.2 and chondrogenic, hypertrophic, and OA\u2010related mediators were determined by real\u2010time quantitative polymerase chain reaction analysis and immunoblotting. In addition, alkaline phosphatase (AP) activity and prostaglandin E<jats:sub>2<\/jats:sub> levels were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>BAPX\u20101\/NKX\u20103.2 expression correlated negatively with expression of chondrocyte hypertrophic markers (RUNX\u20102, COL10A1, AP), cartilage\u2010degrading enzymes (matrix metalloproteinase 13, ADAMTS\u20105), and mediators of inflammation (cyclooxygenase 2, IL\u20106) in healthy and OA chondrocytes, as well as in OA induced chondrocytes. BAPX\u20101\/NKX\u20103.2 positivity was diminished in articular chondrocytes in the knee joints of mice with experimental OA. Knockdown of BAPX\u20101\/NKX\u20103.2 in HACs did not influence the expression of SOX9, COL2A1, or aggrecan, but led to an acute hypertrophic shift in the HAC phenotype. Overexpression of BAPX\u20101\/NKX\u20103.2 decreased hypertrophic gene expression in HACs. Furthermore, the hypertrophic OA chondrocyte phenotype could be counteracted by overexpression of BAPX\u20101\/NKX\u20103.2 and by BMP\u20107 in a BAPX\u20101\/NKX\u20103.2 dependent manner.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings indicate that BAPX\u20101\/NKX\u20103.2 is a molecular switch that is involved in controlling the hypertrophic phenotype of the postdevelopmental (OA) articular chondrocyte.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39293","type":"journal-article","created":{"date-parts":[[2015,8,5]],"date-time":"2015-08-05T20:34:44Z","timestamp":1438806884000},"page":"2944-2956","source":"Crossref","is-referenced-by-count":51,"title":["BAPX\u20101\/NKX\u20103.2 Acts as a Chondrocyte Hypertrophy Molecular Switch in Osteoarthritis"],"prefix":"10.1002","volume":"67","author":[{"given":"Marjolein M. J.","family":"Caron","sequence":"first","affiliation":[{"name":"Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter J.","family":"Emans","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Don A. M.","family":"Surtel","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"van der Kraan","sequence":"additional","affiliation":[{"name":"Radboud University Medical Centre  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lodewijk W.","family":"van Rhijn","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim J. M.","family":"Welting","sequence":"additional","affiliation":[{"name":"Maastricht University Medical Centre  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,10,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34453"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2613.2009.00676.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar3117"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01657"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2011.12.003"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24843"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2741\/s266"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2010.03.001"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.174"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.12.024"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605170103"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/17.19.5718"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00695-08"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.504"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2013.01.009"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2009.03.008"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411144200"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2012.06.016"},{"key":"e_1_2_7_20_1","first-page":"19","article-title":"Degenerative knee joint lesions in mice after a single intra\u2010articular collagenase injection: a new model of osteoarthritis","volume":"71","author":"Kraan PM","year":"1990","journal-title":"J Exp Pathology"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03369"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2443.2000.00339.x"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00039-9"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02258"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00240"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(97)00520-9"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1008002"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.11.005"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1186\/1559-0275-11-6"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2011.0083"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1186\/1749-799X-7-10"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00264-012-1724-1"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034703"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20211"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fart.39293","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.39293","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:26:30Z","timestamp":1759955190000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.39293"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,28]]},"references-count":33,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2015,11]]}},"alternative-id":["10.1002\/art.39293"],"URL":"https:\/\/doi.org\/10.1002\/art.39293","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,28]]}}}