RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21CIP1

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Uma SankarMichael C Ostrowski

Abstract

The coordination of cell cycle progression and osteoclast differentiation by RANKL signaling was studied. Experiments with mouse genetic models revealed that RANKL promoted cell cycle withdrawal of osteoclast precursors dependent on the cyclin kinase inhibitor p27-KIP1, but that both p27-KIP1 and p21-CIP1 were required for osteoclast differentiation. These cyclin inhibitors may directly regulate osteoclast differentiation in addition to regulating cell cycle withdrawal. RANKL stimulates mononuclear precursor cells of the myeloid lineage to differentiate into multinuclear osteoclasts, thus providing a system to study the fundamental problem of coordination of cell cycle progression with cell differentiation. Mice that lack expression of functional cyclin inhibitors p27KIP1and p21CIP1 were used to study cell cycle progression and differentiation of osteoclast precursors in vitro and in vivo. Experiments with cells derived from p27KIP1- and p21CIP1-deficient mice indicated that p27KIP1 function alone was necessary for RANKL-mediated cell cycle withdrawal by osteoclast precursors, but osteoclasts from mice with single mutations in either of these two genes differentiated normally. In contrast, p21/p27 double knockout mice developed...Continue Reading

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