p57(Kip2) is an essential regulator of vitamin D receptor-dependent mechanisms

A cyclin-dependent kinase (CDK) inhibitor, p57(Kip2), is an important molecule involved in bone development; p57(Kip2)-deficient (p57-/-) mice display neonatal lethality resulting from abnormal bone formation and cleft palate. The modulator 1α,25-dihydroxyvitamin D(3) (l,25-(OH)(2)VD(3)) 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(Kip2) in the 1,25-(OH)(2)VD(3)-regulated differentiation of osteoblasts because p57(Kip2) is associated with the vitamin D receptor (VDR). Additionally, 1,25-(OH)(2)VD(3) treatment increased p57(KIP2) expression and induced the colocalization of p57(KIP2) 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)(2)VD(3) upregulated the p57(Kip2) 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)(2)VD(3)-treated osteoblasts revealed a decreased efficiency of 1,25-(OH)(2)VD(3)-stimulated osteoclastogenesis in p57-/- cells. Based on these results, p57(Kip2) might function as a mediator of 1,25-(OH)(2)VD(3) signaling, thereby enabling sufficient VDR activation for osteoblast maturation.