Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis
Cannabinoid Receptor 2 Agonist Prevents Local and Systemic Inflammatory Bone Destruction in Rheumatoid Arthritis
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大麻素受体 2 激动剂可预防类风湿性关节炎的局部和全身炎症性骨破坏
DOI：
10.1002/jbmr.3637
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发表时间：
2019
影响因子：
6.2
通讯作者：
Geng Dechun
中科院分区：
文献类型：
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作者：
Zhu Mo;Yu Binqin;Bai Jiaxiang;Wang Ximing;Guo Xiaobin;Liu Yu;Lin Jiayi;Hu Su;Zhang Wen;Tao Yunxia;Hu Chunhong;Yang Huilin;Xu Yaozeng;Geng Dechun
大麻素受体2（CB 2）已被认为是炎症和恶性骨质溶解的重要临床调节因子。在这里，我们观察到CB 2在胶原诱导关节炎（CIA）小鼠滑膜和骨组织中的表达明显高于非炎症滑膜和骨组织。CB 2选择性激动剂（JWH 133）而非拮抗剂（SR 144528）可抑制小鼠CIA，且无毒性作用，如滑膜增生、炎症反应、软骨损伤以及关节周围和全身骨破坏减少所示。JWH 133治疗减少了促炎性M1样巨噬细胞的浸润，并使巨噬细胞从M1表型复极化为M2表型。同样，CB 2的激活增加了抗炎细胞因子白细胞介素（IL）-10的表达，并减少了促炎细胞因子的表达，包括肿瘤坏死因子-α（TNF-α），IL-1β和IL-6。此外，JWH 133治疗减弱了破骨细胞形成和骨吸收，并降低了CIA小鼠和破骨细胞前体中核因子-κB（NF-κB）配体（RANKL）、基质金属肽酶-9（MMP-9）、抗酒石酸酸性磷酸酶（TRAP）、组织蛋白酶K（CTSK）和活化T细胞核因子1（NFAT-1）的受体活化剂的表达，SR 144528预处理可明显阻断上述作用。从机制上讲，JWH 133抑制破骨细胞前体中RANKL诱导的NF-κB活化。我们发现JWH 133通过抑制破骨细胞生成和调节炎症反应来改善CIA小鼠的病理性骨破坏，从而突出了其作为人类类风湿性关节炎治疗的潜力。© 2018美国骨与矿物质研究学会。
Cannabinoid receptor 2 (CB2) has been implicated as an important clinical regulator of inflammation and malignant osteolysis. Here, we observed that CB2 expression was markedly higher in the collagen‐induced arthritis (CIA) mice synovium and bone tissues than in the noninflamed synovium and bone tissues. The CB2 selective agonist (JWH133) but not antagonist (SR144528) suppressed CIA in mice without toxic effects, as demonstrated by the decreased synovial hyperplasia, inflammatory responses, cartilage damage, and periarticular and systemic bone destruction. JWH133 treatment decreased the infiltration of pro‐inflammatory M1‐like macrophages and repolarized macrophages from the M1 to M2 phenotype. Similarly, activation of CB2 increased the expression of anti‐inflammatory cytokine interleukin (IL)‐10 and reduced the expression of pro‐inflammatory cytokines, including tumor necrosis factor‐α (TNF‐α), IL‐1β, and IL‐6. In addition, JWH133 treatment attenuated osteoclast formation and osteoclastic bone resorption, and reduced the expression of receptor activators of the nuclear factor‐κB (NF‐κB) ligand (RANKL), matrix metallopeptidase‐9 (MMP‐9), tartrate‐resistant acid phosphatase (TRAP), cathepsin K (CTSK), and nuclear factor of activated T‐cells 1 (NFAT‐1) in CIA mice and osteoclast precursors, which were obviously blocked by pretreatment with SR144528. Mechanistically, JWH133 inhibited RANKL‐induced NF‐κB activation in the osteoclast precursors. We found that JWH133 ameliorates pathologic bone destruction in CIA mice via the inhibition of osteoclastogenesis and modulation of inflammatory responses, thereby highlighting its potential as a treatment for human rheumatoid arthritis. © 2018 American Society for Bone and Mineral Research.