Role of MKP-1 in Osteoclasts and Bone Homeostasis
Role of MKP-1 in Osteoclasts and Bone Homeostasis
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DOI：
10.2353/ajpath.2009.090035
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发表时间：
2009-10-01
影响因子：
6
通讯作者：
Vignery, Agnes
中科院分区：
文献类型：
--
作者：
Carlson, Jodi;Cui, Weiguo;Vignery, Agnes
骨量是通过成骨细胞和破骨细胞的互补活动来维持的，但成骨细胞和破骨细胞的分化都涉及丝裂原活化蛋白激酶(WAPK)途径。MAPK受一组称为MAPK磷酸酶(MKPs)的双特异性磷酸酶家族的负性调节。MKP-1是一种应激反应的MKP，可使MAPKs失活，并在巨噬细胞中发挥核心作用；然而，MKP-1是否在维持骨量中发挥作用仍有待研究。我们在这里显示，使用遗传学方法，MKP-1(-/-)雌性小鼠表现出轻微的骨量减少。我们发现MKP-1(+/+)和MKP-1(-/-)小鼠在卵巢切除后有相同水平的骨丢失，尽管MKP-1(-/-)小鼠的破骨细胞较少，这表明MKP-1(-/-)破骨细胞过度活跃。事实上，mkp1的缺失导致了破骨细胞的深刻激活；在体内，对局部脂多糖(LPS)注射的反应。这些结果提示MKP-1在破骨细胞中的作用，破骨细胞起源于巨噬细胞的融合。核因子-kappa B受体激活剂配体诱导MKP-1的表达，来自MKP-1(-/-)小鼠的破骨细胞具有更强的吸收活性。最后，核因子-kappa B受体激活剂配体诱导的p38MAPK和c-Jun NH2末端激酶活性在来自MKP-1(-/-)小鼠的破骨细胞中得到增强。综上所述，这些结果表明MKP-1通过负性调节MAPK依赖的破骨细胞信号而在维持骨量中发挥作用。(Am J Pathol2009175：15641573；DOI：10.2353/ajpath.2009.090035)
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 (WAPK) 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-kappa B ligand induced the expression for MKP-1, and osteoclasts derived from mkp-1(-/-) mice had increased resorptive activity. Finally, receptor activator of nuclear factor-kappa B 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. (Am J Pathol 2009, 175:1564-1573; DOI: 10.2353/ajpath.2009.090035)