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- Title
p57<sup>Kip2</sup> is an essential regulator of vitamin D receptor-dependent mechanisms.
- Authors
Takahashi, Katsuhiko; Amano, Hitoshi; Urano, Tomohiko; Li, Minqi; Oki, Meiko; Aoki, Kazuhiro; Amizuka, Norio; Nakayama, Keiichi I.; Nakayama, Keiko; Udagawa, Nobuyuki; Higashi, Nobuaki
- Abstract
A cyclin-dependent kinase (CDK) inhibitor, p57Kip2, is an important molecule involved in bone development; p57Kip2-deficient (p57-/-) mice display neonatal lethality resulting from abnormal bone formation and cleft palate. The modulator 1α,25-dihydroxyvitamin D3 (l,25-(OH)2VD3) has shown the potential to suppress the proliferation and induce the differentiation of normal and tumor cells. The current study assessed the role of p57Kip2 in the 1,25-(OH)2VD3-regulated differentiation of osteoblasts because p57Kip2 is associated with the vitamin D receptor (VDR). Additionally, 1,25-(OH)2VD3 treatment increased p57KIP2 expression and induced the colocalization of p57KIP2 with VDR in the osteoblast nucleus. Primary p57-/- osteoblasts exhibited higher proliferation rates with Cdk activation than p57+/+ cells. A lower level of nodule mineralization was observed in p57-/- osteoblasts than in p57+/+ cells. In p57+/+ osteoblasts, 1,25-(OH)2VD3 upregulated the p57Kip2 and opn mRNA expression levels, while the opn expression levels were significantly decreased in p57-/- cells. The osteoclastogenesis assay performed using bone marrow cocultured with 1,25-(OH)2VD3-treated osteoblasts revealed a decreased efficiency of 1,25-(OH)2VD3-stimulated osteoclastogenesis in p57-/- cells. Based on these results, p57Kip2 might function as a mediator of 1,25-(OH)2VD3 signaling, thereby enabling sufficient VDR activation for osteoblast maturation.
- Subjects
VITAMIN D receptors; VITAMIN D; OSTEOBLASTS; BONE growth; CLEFT palate; GENE expression; BONE marrow
- Publication
PLoS ONE, 2023, Vol 17, Issue 2, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0276838