Binder Nikolaus B, Niederreiter Birgit, Hoffmann Oskar, Stange Richard, Pap Thomas, Stulnig Thomas M, Mack Matthias, Erben Reinhold G, Smolen Josef S, Redlich Kurt
Division of Rheumatology, Medical University Vienna, Vienna, Austria.
Nat Med. 2009 Apr;15(4):417-24. doi: 10.1038/nm.1945. Epub 2009 Mar 29.
Understanding the mechanisms of osteoclastogenesis is crucial for developing new drugs to treat diseases associated with bone loss, such as osteoporosis. Here we report that the C-C chemokine receptor-2 (CCR2) is crucially involved in balancing bone mass. CCR2-knockout mice have high bone mass owing to a decrease in number, size and function of osteoclasts. In normal mice, activation of CCR2 in osteoclast progenitor cells results in both nuclear factor-kappaB (NF-kappaB) and extracellular signal-related kinase 1 and 2 (ERK1/2) signaling but not that of p38 mitogen-activated protein kinase or c-Jun N-terminal kinase. The induction of NF-kappaB and ERK1/2 signaling in turn leads to increased surface expression of receptor activator of NF-kappaB (RANK, encoded by Tnfrsf11a), making the progenitor cells more susceptible to RANK ligand-induced osteoclastogenesis. In ovariectomized mice, a model of postmenopausal osteoporosis, CCR2 is upregulated on wild-type preosteoclasts, thus increasing the surface expression of RANK on these cells and their osteoclastogenic potential, whereas CCR2-knockout mice are resistant to ovariectomy-induced bone loss. These data reveal a previously undescribed pathway by which RANK, osteoclasts and bone homeostasis are regulated in health and disease.
了解破骨细胞生成机制对于开发治疗与骨质流失相关疾病（如骨质疏松症）的新药至关重要。在此，我们报告C-C趋化因子受体2（CCR2）在平衡骨量方面起着关键作用。CCR2基因敲除小鼠由于破骨细胞数量、大小和功能的减少而具有高骨量。在正常小鼠中，破骨细胞祖细胞中CCR2的激活会导致核因子-κB（NF-κB）以及细胞外信号调节激酶1和2（ERK1/2）信号通路的激活，但不会导致p38丝裂原活化蛋白激酶或c-Jun氨基末端激酶信号通路的激活。NF-κB和ERK1/2信号通路的诱导反过来会导致NF-κB受体激活剂（RANK，由Tnfrsf11a编码）的表面表达增加，使祖细胞更容易受到RANK配体诱导的破骨细胞生成。在绝经后骨质疏松症模型的去卵巢小鼠中，野生型前破骨细胞上的CCR2上调，从而增加这些细胞上RANK的表面表达及其破骨细胞生成潜力，而CCR2基因敲除小鼠对去卵巢诱导的骨质流失具有抗性。这些数据揭示了一条此前未被描述的途径，通过该途径在健康和疾病状态下调节RANK、破骨细胞和骨稳态。
