{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:03:40Z","timestamp":1789506220530,"version":"build-2803163510"},"reference-count":126,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T00:00:00Z","timestamp":1649116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006315","name":"Reumafonds","doi-asserted-by":"publisher","award":["16-1-40"],"award-info":[{"award-number":["16-1-40"]}],"id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>During osteoarthritis (OA), hypertrophy-like chondrocytes contribute to the disease process. TGF-\u03b2\u2019s signaling pathways can contribute to a hypertrophy(-like) phenotype in chondrocytes, especially at high doses of TGF-\u03b2. In this study, we examine which transcription factors (TFs) are activated and involved in TGF-\u03b2-dependent induction of a hypertrophy-like phenotype in human OA chondrocytes. We found that TGF-\u03b2, at levels found in synovial fluid in OA patients, induces hypertrophic differentiation, as characterized by increased expression of RUNX2, COL10A1, COL1A1, VEGFA and IHH. Using luciferase-based TF activity assays, we observed that the expression of these hypertrophy genes positively correlated to SMAD3:4, STAT3 and AP1 activity. Blocking these TFs using specific inhibitors for ALK-5-induced SMAD signaling (5 \u00b5M SB-505124), JAK-STAT signaling (1 \u00b5M Tofacitinib) and JNK signaling (10 \u00b5M SP-600125) led to the striking observation that only SB-505124 repressed the expression of hypertrophy factors in TGF-\u03b2-stimulated chondrocytes. Therefore, we conclude that ALK5 kinase activity is essential for TGF-\u03b2-induced expression of crucial hypertrophy factors in chondrocytes.<\/jats:p>","DOI":"10.3390\/cells11071232","type":"journal-article","created":{"date-parts":[[2022,4,5]],"date-time":"2022-04-05T11:26:07Z","timestamp":1649157967000},"page":"1232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Identification of Transcription Factors Responsible for a Transforming Growth Factor-\u03b2-Driven Hypertrophy-like Phenotype in Human Osteoarthritic Chondrocytes"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3245-7537","authenticated-orcid":false,"given":"Nathalie G. M.","family":"Thielen","sequence":"first","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margot","family":"Neefjes","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elly L.","family":"Vitters","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk M.","family":"van Beuningen","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjen B.","family":"Blom","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marije I.","family":"Koenders","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L. E. M.","family":"van Lent","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fons A. J.","family":"van de Loo","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda N.","family":"Blaney Davidson","sequence":"additional","affiliation":[{"name":"Department of Experimental Rheumatology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-4884","authenticated-orcid":false,"given":"Arjan P. 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