The cell cycle regulator p27(kip1) contributes to growth and differentiation of osteoblasts

The cyclin-dependent kinase (cdk) inhibitors are key regulators of cell cyc le progression. p27 and p21 are members of the Cip/Kip family of cdk inhibi tors and regulate cell growth by inactivating cell cycle stage-specific CDK -cyclin complexes. Because down-regulation of osteoprogenitor proliferation is a critical step for osteoblast differentiation, we investigated express ion of p27 and p21 during development of the osteoblast phenotype in rat ca lvarial osteoblasts and in proliferating and growth-inhibited osteosarcoma ROS 17/2.8 cells. Expression of these proteins indicates that p21, which pr edominates in the growth period, is related to proliferation control. p27 l evels are maximal postproliferatively, suggesting a role in the transition from cell proliferation to osteoblast differentiation. We directly examined the role of p27 during differentiation of osteoprogenitor cells derived fr om the bone marrow (BM) of p27(-/-) mice. BM cells from p27 null mice exhib ited increased proliferative activity compared with BM cells from wild-type mice and formed an increased number and larger size of osteoblastic coloni es, which further differentiated to the mineralization stage. Although p27( -/-) adherent marrow cells proliferate faster, they retain competency for d ifferentiation, which may result, in part, from observed higher p21 levels compared with wild type. Histological studies of p27(-/-) bones also showed an increased cellularity in the marrow cavity compared with the p27(+/+). The increased proliferation in bone does not lead to tumorigenesis, in cont rast to observed adenomas in the null mice. Taken together, these findings indicate that p27 plays a key role in regulating osteoblast differentiation by controlling proliferation-related events in bone cells.