Role of MKP-1 in osteoclasts and bone homeostasis

Jodi Carlson, Weiguo Cui, Qing Zhang, Xiaoqing Xu, Fatih Mercan, Anton M. Bennett, Agnès Vignery

Research output: Contribution to journalArticlepeer-review


Bone mass is maintained through the complementary activities of osteoblasts and osteoclasts; yet differentiation of either osteoblasts and osteoclasts engages the mitogen-activated protein kinase (MAPK) pathway. The MAPKs are negatively regulated by a family of dual-specificity phosphatases known as the MAPK phosphatases (MKPs). MKP-1 is a stress-responsive MKP that inactivates the MAPKs and plays a central role in macrophages; however, whether MKP-1 plays a role in the maintenance of bone mass has yet to be investigated. We show here, using a genetic approach, that mkp-1-/- female mice exhibited slightly reduced bone mass. We found that mkp-1+/+ and mkp-1 -/- mice had equivalent levels of bone loss after ovariectomy despite mkp-1-/- mice having fewer osteoclasts, suggesting that mkp-1 -/- osteoclasts are hyperactive. Indeed, deletion of MKP1 led to a profound activation of osteoclasts in vivo in response to local lipopolysaccharide (LPS) injection. These results suggest a role for MKP-1 in osteoclasts, which originate from the fusion of macrophages. In support of these observations, receptor activator for nuclear factor-κB ligand induced the expression for MKP-1, and osteoclasts derived from mkp-1-/- mice had increased resorptive activity. Finally, receptor activator of nuclear factor-κB ligand-induced p38 MAPK and c-Jun NH2-terminal kinase activities were enhanced in osteoclasts derived from mkp-1-/- mice. Taken together, these results show that MKP-1 plays a role in the maintenance of bone mass and does so by negatively regulating MAPK-dependent osteoclast signaling.

Original languageEnglish (US)
Pages (from-to)1564-1573
Number of pages10
JournalAmerican Journal of Pathology
Issue number4
StatePublished - 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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