Peripheral cannabinoid receptor, CB2, regulates bone mass
Peripheral cannabinoid receptor, CB2, regulates bone mass
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DOI：
10.1073/pnas.0504187103
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发表时间：
2006-01-17
影响因子：
11.1
通讯作者：
Bab, I
中科院分区：
文献类型：
--
作者：
Ofek, O;Karsak, M;Bab, I
内源性大麻素结合并激活两个G蛋白偶联受体，主要是中枢大麻素受体1(CB1)和外周大麻素受体2(CB2)。虽然CB1介导大麻素的精神药物、止痛和止痛作用，但CB2最近被认为与肝纤维化和动脉粥样硬化的调节有关。在这里，我们显示CB2缺乏的小鼠有明显加速的与年龄相关的骨小梁丢失和皮质扩张，尽管皮质厚度保持不变。这些变化使人联想到人类的骨质疏松症，可能是由于骨小梁和皮质骨重塑的不同调节所致。CB2(-/-)表型的特征还包括小梁成骨细胞(骨形成细胞)活性增加，破骨细胞(骨吸收细胞)数量增加，骨干成骨细胞前体细胞数量显著减少。CB2在成骨细胞、骨细胞和破骨细胞中表达。一种不具有任何精神药物作用的CB2特异性激动剂增加皮质内成骨细胞的数量和活性，并抑制骨小梁破骨细胞的生成，显然是通过抑制骨髓来源的成骨细胞/基质细胞中破骨细胞前体和核因子-kappaB受体激活剂的表达而实现的。同一激动剂通过分别抑制破骨细胞数量和刺激皮质内骨形成，减轻卵巢切除所致的骨丢失，并显著刺激皮质厚度。这些结果表明，内源性大麻素系统是通过成骨细胞和破骨细胞CB2信号维持正常骨量所必需的。因此，CB2为诊断和治疗骨质疏松症提供了一个分子靶点，骨质疏松症是发达国家最常见的退行性疾病。
The endogenous cannabinoids bind to and activate two G protein-coupled receptors, the predominantly central cannabinoid receptor type 1 (CB1) and peripheral cannabinoid receptor type 2 (CB2). Whereas CB1 mediates the cannabinoid psychotropic, analgesic, and orectic effects, CB2 has been implicated recently in the regulation of liver fibrosis and atherosclerosis. Here we show that CB2-deficient mice have a markedly accelerated age-related trabecular bone loss and cortical expansion, although cortical thickness remains unaltered. These changes are reminiscent of human osteoporosis and may result from differential regulation of trabecular and cortical bone remodeling. The CB2(-/-) phenotype is also characterized by increased activity of trabecular osteoblasts (bone-forming cells), increased osteoclast (the bone-resorbing cell) number, and a markedly decreased number of diaphyseal osteoblast precursors. CB2 is expressed in osteoblasts, osteocytes, and osteoclasts. A CB2-specific agonist that does not have any psychotropic effects enhances endocortical osteoblast number and activity and restrains trabecular osteoclastogenesis, apparently by inhibiting proliferation of osteoclast precursors and receptor activator of NF-kappa B ligand expression in bone marrow-derived osteoblasts/stromal cells. The same agonist attenuates ovariectomy-induced bone loss and markedly stimulates cortical thickness through the respective suppression of osteoclast number and stimulation of endocortical bone formation. These results demonstrate that the endlocannabinoid system is essential for the maintenance of normal bone mass by osteoblastic and osteoclastic CB2 signaling. Hence, CB2 offers a molecular target for the diagnosis and treatment of osteoporosis, the most prevalent degenerative disease in developed countries.