Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy.
FASEB J. 2011 Apr;25(4):1264-74. doi: 10.1096/fj.10-169854. Epub 2011 Jan 13.
Defects in bone homeostasis are a major health problem. Osteoclast differentiation and activation have a crucial role in bone remodeling in health and disease. Osteoclasts are bone-resorbing cells derived from mononuclear phagocyte progenitors. The key event in osteoclast formation is fusion of mononucleate precursors to form mature multinucleated osteclasts. Here we provide evidence of an absolute requirement for the P2X7 receptor, ATP release, and adenosine signaling in human osteoclast formation, as shown by the following findings: macrophage-colony stimulating factor/receptor activator for nuclear factor-κB ligand (M-CSF/RANKL)-stimulated fusion of human monocytes is fully prevented by an anti-P2X7 mAb, by specific P2X7 pharmacological antagonists, or by inhibition of CD39/NTPDase; fusion-competent monocytes release ATP via the P2X7 receptor; accelerated degradation of released ATP by addition of either apyrase or hexokinase strongly increases fusion; removal of extracellular adenosine by adenosine deaminase blocks, while addition of exogenous adenosine strongly potentiates, fusion; and pharmacologic stimulation of the adenosine A2A receptor increases, while selective A2A blockade inhibits, fusion. These results show that the purinergic axis plays a crucial and as yet undescribed role in osteoclast formation and reconcile previous evidence advocating a key role for either ATP or adenosine receptors in multinucleated giant cell formation.
骨稳态缺陷是一个主要的健康问题。破骨细胞分化和激活在健康和疾病中的骨重塑中起着至关重要的作用。破骨细胞是来源于单核吞噬细胞祖细胞的骨吸收细胞。破骨细胞形成的关键事件是单核细胞前体融合形成成熟的多核破骨细胞。在这里，我们提供了证据表明 P2X7 受体、ATP 释放和腺苷信号在人类破骨细胞形成中是绝对必需的，如下发现所示：巨噬细胞集落刺激因子/核因子-κB 配体（M-CSF/RANKL）刺激的人单核细胞融合完全被抗 P2X7 mAb、特定的 P2X7 药理学拮抗剂或 CD39/NTPDase 抑制所阻止；融合相容的单核细胞通过 P2X7 受体释放 ATP；通过添加 apyrase 或己糖激酶加速释放的 ATP 的降解强烈增加融合；通过添加腺苷脱氨酶去除细胞外腺苷会阻止融合，而添加外源性腺苷则强烈增强融合；嘌呤能轴在破骨细胞形成中起着关键作用，而目前尚未描述，这与先前主张 ATP 或腺苷受体在多核巨细胞形成中起关键作用的证据相吻合。
