Ofek Orr, Karsak Meliha, Leclerc Nathalie, Fogel Meirav, Frenkel Baruch, Wright Karen, Tam Joseph, Attar-Namdar Malka, Kram Vardit, Shohami Esther, Mechoulam Raphael, Zimmer Andreas, Bab Itai
Bone Laboratory, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):696-701. doi: 10.1073/pnas.0504187103. Epub 2006 Jan 9.
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-kappaB 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 endocannabinoid 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.
内源性大麻素与两种G蛋白偶联受体结合并激活它们，即主要位于中枢的1型大麻素受体（CB1）和外周的2型大麻素受体（CB2）。CB1介导大麻素的精神作用、镇痛作用和食欲增进作用，而CB2最近被认为参与肝纤维化和动脉粥样硬化的调节。我们在此表明，CB2基因缺陷小鼠与年龄相关的小梁骨丢失和皮质骨扩张明显加速，尽管皮质厚度保持不变。这些变化类似于人类骨质疏松症，可能是由于小梁骨和皮质骨重塑的差异调节所致。CB2基因敲除小鼠的表型还表现为小梁成骨细胞（骨形成细胞）活性增加、破骨细胞（骨吸收细胞）数量增加以及骨干成骨细胞前体细胞数量明显减少。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作用的CB2特异性激动剂可增加内皮质成骨细胞数量和活性，并抑制小梁破骨细胞生成，这显然是通过抑制破骨细胞前体细胞的增殖以及骨髓来源的成骨细胞/基质细胞中核因子κB受体活化因子配体的表达来实现的。相同的激动剂可减轻卵巢切除诱导的骨丢失，并通过分别抑制破骨细胞数量和刺激内皮质骨形成来显著增加皮质厚度。这些结果表明，内源性大麻素系统通过成骨细胞和破骨细胞的CB2信号传导对于维持正常骨量至关重要。因此，CB2为骨质疏松症（发达国家最常见的退行性疾病）的诊断和治疗提供了一个分子靶点。
