TY - JOUR
T1 - Role of MKP-1 in osteoclasts and bone homeostasis
AU - Carlson, Jodi
AU - Cui, Weiguo
AU - Zhang, Qing
AU - Xu, Xiaoqing
AU - Mercan, Fatih
AU - Bennett, Anton M.
AU - Vignery, Agnès
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=73549120650&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73549120650&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2009.090035
DO - 10.2353/ajpath.2009.090035
M3 - Article
C2 - 19762714
AN - SCOPUS:73549120650
SN - 0002-9440
VL - 175
SP - 1564
EP - 1573
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 4
ER -