Role of MKP-1 in osteoclasts and bone homeostasis.
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-kappaB ligand induced the expression for MKP-1, and osteoclasts derived from mkp-1(-/-) mice had increased resorptive activity. Finally, receptor activator of nuclear factor-kappaB 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.
Carlson
Jodi
J
Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Cui
Weiguo
W
Zhang
Qing
Q
Xu
Xiaoqing
X
Mercan
Fatih
F
Bennett
Anton M
AM
Vignery
Agnès
A
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000201:enzymology / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004967:Estrogens; D005260:Female; D006706:Homeostasis; D007267:Injections; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010052:Ovariectomy; D053245:RANK Ligand / Q000494:pharmacology
D004967:Estrogens; D008070:Lipopolysaccharides; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse