RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21 CIP1

Uma Sankar, Krupen Patel, Thomas J. Rosol, Michael C. Ostrowski

Research output: Contribution to journalArticle

39 Citations (Scopus)

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. Introduction: 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. Materials and Methods: Mice that lack expression of functional cyclin inhibitors p27KIP1 and p21CIP1 were used to study cell cycle progression and differentiation of osteoclast precursors in vitro and in vivo. Results and Conclusions: 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 osteopetrosis, with fewer osteoclasts that exhibited lower TRACP activity and abnormal cell morphology present in long bone. Moreover, isolated osteoclast progenitors from p21/p27 double knockout mice were defective in RANKL-mediated differentiation in vitro, expressing low levels of osteoclast-specific genes like TRACP and cathepsin K. Taken together, these data suggest p27KIP1 and p21CIP1 play roles in osteoclast differentiation in response to RANKL signaling distinct from their roles in promoting cell cycle withdrawal.

Original languageEnglish (US)
Pages (from-to)1339-1348
Number of pages10
JournalJournal of Bone and Mineral Research
Volume19
Issue number8
DOIs
StatePublished - Aug 2004
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase Inhibitor p21
Osteoclasts
Cell Differentiation
Cell Cycle
Cyclins
Knockout Mice
Cathepsin K
Cyclin-Dependent Kinase Inhibitor p27
Osteopetrosis
Genetic Models
Cell Lineage
Genes

Keywords

  • Cyclin-dependent kinase inhibitors
  • Modeling and remodeling
  • Osteopetrosis
  • RANKL

ASJC Scopus subject areas

  • Surgery

Cite this

RANKL coordinates cell cycle withdrawal and differentiation in osteoclasts through the cyclin-dependent kinase inhibitors p27KIP1 and p21 CIP1. / Sankar, Uma; Patel, Krupen; Rosol, Thomas J.; Ostrowski, Michael C.

In: Journal of Bone and Mineral Research, Vol. 19, No. 8, 08.2004, p. 1339-1348.

Research output: Contribution to journalArticle

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