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The modulator 1\u03b1,25-dihydroxyvitamin D<jats:sub>3<\/jats:sub> (l,25-(OH)<jats:sub>2<\/jats:sub>VD<jats:sub>3<\/jats:sub>) has shown the potential to suppress the proliferation and induce the differentiation of normal and tumor cells. The current study assessed the role of p57<jats:sup>Kip2<\/jats:sup> in the 1,25-(OH)<jats:sub>2<\/jats:sub>VD<jats:sub>3<\/jats:sub>-regulated differentiation of osteoblasts because p57<jats:sup>Kip2<\/jats:sup> is associated with the vitamin D receptor (VDR). Additionally, 1,25-(OH)<jats:sub>2<\/jats:sub>VD<jats:sub>3<\/jats:sub> treatment increased p57<jats:sup>KIP2<\/jats:sup> expression and induced the colocalization of p57<jats:sup>KIP2<\/jats:sup> with VDR in the osteoblast nucleus. Primary <jats:italic>p57<\/jats:italic>-\/- osteoblasts exhibited higher proliferation rates with Cdk activation than <jats:italic>p57+\/+<\/jats:italic> cells. A lower level of nodule mineralization was observed in <jats:italic>p57<\/jats:italic>-\/- osteoblasts than in <jats:italic>p57+\/+<\/jats:italic> cells. In <jats:italic>p57+\/+<\/jats:italic> osteoblasts, 1,25-(OH)<jats:sub>2<\/jats:sub>VD<jats:sub>3<\/jats:sub> upregulated the <jats:italic>p57<\/jats:italic><jats:sup><jats:italic>Kip2<\/jats:italic><\/jats:sup> and <jats:italic>opn<\/jats:italic> mRNA expression levels, while the <jats:italic>opn<\/jats:italic> expression levels were significantly decreased in <jats:italic>p57-\/-<\/jats:italic> cells. The osteoclastogenesis assay performed using bone marrow cocultured with 1,25-(OH)<jats:sub><jats:italic>2<\/jats:italic><\/jats:sub>VD<jats:sub>3<\/jats:sub>-treated osteoblasts revealed a decreased efficiency of 1,25-(OH)<jats:sub><jats:italic>2<\/jats:italic><\/jats:sub>VD<jats:sub>3<\/jats:sub>-stimulated osteoclastogenesis in <jats:italic>p57-\/-<\/jats:italic> cells. Based on these results, p57<jats:sup>Kip2<\/jats:sup> might function as a mediator of 1,25-(OH)<jats:sub>2<\/jats:sub>VD<jats:sub>3<\/jats:sub> signaling, thereby enabling sufficient VDR activation for osteoblast maturation.<\/jats:p>","DOI":"10.1371\/journal.pone.0276838","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T18:33:29Z","timestamp":1676486009000},"page":"e0276838","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["p57Kip2 is an essential regulator of vitamin D receptor-dependent mechanisms"],"prefix":"10.1371","volume":"18","author":[{"given":"Katsuhiko","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7370-4832","authenticated-orcid":true,"given":"Hitoshi","family":"Amano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomohiko","family":"Urano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minqi","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meiko","family":"Oki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norio","family":"Amizuka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-1529","authenticated-orcid":true,"given":"Keiichi I.","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiko","family":"Nakayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nobuyuki","family":"Udagawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6803-6147","authenticated-orcid":true,"given":"Nobuaki","family":"Higashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"pone.0276838.ref001","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1359\/jbmr.0301204","article-title":"The effects of 1\u03b1,25-dihydroxyvitamin D3 on the expression of DNA replication genes","volume":"19","author":"G Eelen","year":"2004","journal-title":"J Bone Miner Res"},{"key":"pone.0276838.ref002","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1101\/gad.9.6.639","article-title":"Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution","volume":"9","author":"MH Lee","year":"1995","journal-title":"Genes Dev"},{"key":"pone.0276838.ref003","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1101\/gad.9.6.650","article-title":"p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene","volume":"9","author":"S Matsuoka","year":"1995","journal-title":"Genes Dev"},{"key":"pone.0276838.ref004","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/0092-8674(92)90249-C","article-title":"Regulation of retinoblastoma protein functions by ectopic expression of human cyclins","volume":"70","author":"P.W. 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