Role of MKP-1 in osteoclasts and bone homeostasis. Am J Pathol 2009 Oct;175(4):1564-73
Date
09/19/2009Pubmed ID
19762714Pubmed Central ID
PMC2751553DOI
10.2353/ajpath.2009.090035Scopus ID
2-s2.0-73549120650 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
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.
Author List
Carlson J, Cui W, Zhang Q, Xu X, Mercan F, Bennett AM, Vignery AMESH terms used to index this publication - Major topics in bold
AnimalsBone Density
Bone Resorption
Bone and Bones
Cell Count
Cell Differentiation
Dual Specificity Phosphatase 1
Enzyme Activation
Estrogens
Female
Homeostasis
Injections
Lipopolysaccharides
Macrophage Colony-Stimulating Factor
Male
Mice
Osteoblasts
Osteoclasts
Ovariectomy
RANK Ligand