Possible involvement of the p57(Kip2) gene in bone metabolism

We previously uncovered that growth stimulation of rat primary osteoblasts by transforming growth factor-beta 1 (TGF-beta 1) resulted in a dramatic de crease in p57(Kip2), a member of cyclin-dependent kinase (CDH) inhibitors, through the proteasomal degradation pathway (Urano et at, J. Biol Chem. 274 , 12197-12200, 1999). Here we demonstrated that the amount of p57 protein i ncreases markedly, when rat calvarial primary osteoblasts treated with 1,25 -dihydroxyvitamin D3 transit from proliferation toward differentiation. Nex t, we have analyzed the association of four amino acids deletion polymorphi sm of p57 and bone mineral density (BMD). The p57 genotype was determined i n 154 postmenopausal Japanese women. When we separated the subjects into tw o groups, one having one or two copies of deletion polymorphism and the oth er without the deletion, the former subjects had higher BMD (Z score of tot al body, 0.67 +/- 0.93 vs 0.23 +/- 0.90, mean +/- standard deviation; P = 0 .021). Taken together, these findings suggest that the p57 regulated in the osteoblast proliferation and differentiation mag play a role in determinat ion of bone mineral density and pathogenesis of osteoporosis. (C) 2000 Acad emic Press.