{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:55:14Z","timestamp":1790628914692,"version":"4.1.0"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T00:00:00Z","timestamp":1485475200000},"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":[[2017,5,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:sec>\n                  <jats:title>\u2003<\/jats:title>\n                  <jats:p>Osteoarthritis (OA) is a multifactorial disease, and recent data suggested that cell cycle\u2013related proteins play a role in OA pathology. Cyclin-dependent kinase (CDK) inhibitor 1 (p21) regulates activation of other CDKs, and recently, we reported that p21 deficiency induced susceptibility to OA induced by destabilization of the medial meniscus (DMM) surgery through STAT3-signaling activation. However, the mechanisms associated with why p21 deficiency led to susceptibility to OA by the STAT3 pathway remain unknown. Therefore, we focused on joint inflammation to determine the mechanisms associated with p21 function during in vitro and in vivo OA progression. p21-knockout (p21\u2212\/\u2212) mice were used to develop an in vivo OA model, and C57BL\/6 (p21+\/+) mice with the same background as the p21\u2212\/\u2212 mice were used as controls. Morphogenic changes were measured using micro-CT, IL-1\u03b2 serum levels were detected by ELISA, and histological or immunohistological analyses were performed. Our results indicated that p21-deficient DMM-model mice exhibited significant subchondral bone destruction and cartilage degradation compared with wild-type mice. Immunohistochemistry results revealed p21\u2212\/\u2212 mice susceptibility to OA changes accompanied by macrophage infiltration and enhanced MMP-3 and MMP-13 expression through IL-1\u03b2-induced NF-\u03baB signaling. p21\u2212\/\u2212 mice also showed subchondral bone destruction according to micro-CT analysis, and cathepsin K staining revealed increased numbers of osteoclasts. Furthermore, p21\u2212\/\u2212 mice displayed increased serum IL-1\u03b2 levels, and isolated chondrocytes from p21\u2212\/\u2212 mice indicated elevated MMP-3 and MMP-13 expression with phosphorylation of I\u03baB kinase complex in response to IL-1\u03b2 stimulation, whereas treatment with a specific p-I\u03baB kinase inhibitor attenuated MMP-3 and MMP-13 expression. Our results indicated that p21-deficient DMM mice were susceptible to alterations in OA phenotype, including enhanced osteoclast expression, macrophage infiltration, and MMP expression through IL-1\u03b2-induced NF-\u03baB signaling, suggesting that p21 regulation may constitute a possible therapeutic strategy for OA treatment. \u00a9 2017 American Society for Bone and Mineral Research.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1002\/jbmr.3080","type":"journal-article","created":{"date-parts":[[2017,1,27]],"date-time":"2017-01-27T16:57:35Z","timestamp":1485536255000},"page":"991-1001","source":"Crossref","is-referenced-by-count":34,"title":["Cyclin-Dependent Kinase Inhibitor-1-Deficient Mice are Susceptible to Osteoarthritis Associated with Enhanced Inflammation"],"prefix":"10.1093","volume":"32","author":[{"given":"Shinsuke","family":"Kihara","sequence":"first","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinya","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Kanzaki","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Takayama","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Chinzei","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Iwasa","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of MedicineKobeHyogoJapan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiko","family":"Haneda","sequence":"additional","affiliation":[{"name":"Department of Orthopedic SurgeryKobe University Graduate School of 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