Li Xin, Qin Ling, Bergenstock Marika, Bevelock Laura M, Novack Deborah V, Partridge Nicola C
Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
J Biol Chem. 2007 Nov 9;282(45):33098-106. doi: 10.1074/jbc.M611781200. Epub 2007 Aug 9.
The clinical findings that alendronate blunted the anabolic effect of human parathyroid hormone (PTH) on bone formation suggest that active resorption is involved and enhances the anabolic effect. PTH signals via its receptor on the osteoblast membrane, and osteoclasts are impacted indirectly via the products of osteoblasts. Microarray with RNA from rats injected with human PTH or vehicle showed a strong association between the stimulation of monocyte chemoattractant protein-1 (MCP-1) and the anabolic effects of PTH. PTH rapidly and dramatically stimulated MCP-1 mRNA in the femora of rats receiving daily injections of PTH or in primary osteoblastic and UMR 106-01 cells. The stimulation of MCP-1 mRNA was dose-dependent and a primary response to PTH signaling via the cAMP-dependent protein kinase pathway in vitro. Studies with the mouse monocyte cell line RAW 264.7 and mouse bone marrow proved that osteoblastic MCP-1 can potently recruit osteoclast monocyte precursors and facilitate receptor activator of NF-kappaB ligand-induced osteoclastogenesis and, in particular, enhanced fusion. Our model suggests that PTH-induced osteoblastic expression of MCP-1 is involved in recruitment and differentiation at the stage of multinucleation of osteoclast precursors. This information provides a rationale for increased osteoclast activity in the anabolic effects of PTH in addition to receptor activator of NF-kappaB ligand stimulation to initiate greater bone remodeling.
阿仑膦酸盐削弱人甲状旁腺激素（PTH）对骨形成的合成代谢作用这一临床发现表明，活跃的骨吸收参与其中并增强了合成代谢作用。PTH通过其在成骨细胞膜上的受体发出信号，破骨细胞则通过成骨细胞的产物受到间接影响。对注射人PTH或赋形剂的大鼠的RNA进行微阵列分析显示，单核细胞趋化蛋白-1（MCP-1）的刺激与PTH的合成代谢作用之间存在强烈关联。PTH能迅速且显著地刺激每日接受PTH注射的大鼠股骨中、原代成骨细胞和UMR 106-01细胞中的MCP-1 mRNA。MCP-1 mRNA的刺激呈剂量依赖性，且在体外是对通过环磷酸腺苷依赖性蛋白激酶途径的PTH信号的初级反应。对小鼠单核细胞系RAW 264.7和小鼠骨髓的研究证明，成骨细胞产生的MCP-1能有效地募集破骨细胞单核前体，并促进核因子κB受体激活剂配体诱导的破骨细胞生成，尤其是增强融合。我们的模型表明，PTH诱导的成骨细胞MCP-1表达参与破骨细胞前体多核化阶段的募集和分化。这一信息为PTH合成代谢作用中破骨细胞活性增加提供了理论依据，除了核因子κB受体激活剂配体刺激以启动更大程度的骨重塑外。
