The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo
The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo
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DOI：
10.1073/pnas.0902743106
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发表时间：
2009-09-22
影响因子：
11.1
通讯作者：
Rogers, Michael J.
中科院分区：
文献类型：
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作者：
Whyte, Lauren S.;Ryberg, Erik;Rogers, Michael J.
GPR55 是一种 G 蛋白偶联受体，最近显示可被某些大麻素和溶血磷脂酰肌醇 (LPI) 激活。然而，GPR55 的生理作用仍不清楚。鉴于最近发现大麻素受体 CB1 和 CB2 影响骨代谢，我们研究了 GPR55 在骨生物学中的作用。 GPR55 在人和小鼠破骨细胞和成骨细胞中表达；在人破骨细胞中的表达高于在巨噬细胞祖细胞中的表达。尽管 GPR55 激动剂 O-1602 和 LPI 在体外抑制小鼠破骨细胞形成，但这些配体在体外刺激小鼠和人破骨细胞极化和吸收，并引起 Rho 和 ERK1/2 激活。这些对破骨细胞功能的刺激作用在 GPR55(-/-) 巨噬细胞和 GPR55 拮抗剂大麻二酚 (CBD) 产生的破骨细胞中减弱。此外，用大麻的这种非精神活性成分治疗小鼠可显着减少体内骨吸收。与 GPR55 抑制破骨细胞形成但刺激破骨细胞功能的能力一致，对雄性 GPR55(-/-) 小鼠长骨的组织形态计量学和微计算机断层扫描分析显示，形态上不活跃的破骨细胞数量增加，但小梁骨的体积和厚度显着增加，并且存在未吸收的软骨。这些数据揭示了 GPR55 通过调节破骨细胞数量和功能在骨生理学中的作用。此外，这项研究还揭示了内源性配体 LPI 对破骨细胞的影响以及大麻成分 CBD 对破骨细胞和体内骨转换的影响。
GPR55 is a G protein-coupled receptor recently shown to be activated by certain cannabinoids and by lysophosphatidylinositol (LPI). However, the physiological role of GPR55 remains unknown. Given the recent finding that the cannabinoid receptors CB1 and CB2 affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation in vitro, these ligands stimulated mouse and human osteoclast polarization and resorption in vitro and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55(-/-) macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption in vivo. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55(-/-) mice revealed increased numbers of morphologically inactive osteoclasts but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light an effect of both the endogenous ligand, LPI, on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover in vivo.