Deciphering the role of RANK/RANKL/OPG in skeletal muscle

破译 RANK/RANKL/OPG 在骨骼肌中的作用

• 批准号: RGPIN-2016-05845
• 负责人: Frenette, Jérôme
• 金额: $ 2.55万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=630937
• 关键词: Deciphering; role; RANK; RANKL; OPG

The discovery of RANK/RANKL/OPG the receptor-activator of nuclear factor κB (RANK), the receptor-activator of nuclear factor κB ligand (RANKL), and the osteoprotegerin (OPG) pathway has been among the most important advances in bone biology and disease. RANK/RANKL/OPG form a key cytokine system for regulating osteoclast differentiation and function. RANKL is expressed by osteoblasts while RANK, its receptor, is expressed on pre-osteoclastic cells. The RANK/RANKL interaction induces the formation of multinucleated mature osteoclasts, ultimately causing bone resorption. However, the third protagonist, OPG, is also produced by osteoblasts and exerts an inhibitory effect on pre-osteoclastic differentiation. OPG, by binding to RANKL, inhibits the RANKL/RANK interaction and the subsequent osteoclastogenesis. The fact that OPG-null mice are osteoporotic is testimony to the physiological importance of OPG. OPG also serves as a decoy receptor for the tumour necrosis factor-related apoptosis-inducing ligand and increases cell survival by blocking the pro-apoptotic effects of the RANK/RANKL interaction. OPG is thus a very efficient anti-resorptive and anti-apoptotic agent. However, our recent publication in Am. J. Pathol. (2015) convincingly showed that OPG-Fc completely restores the function of fast-twitch extensor digitorum longus muscles and significantly improves the function of slow-twitch soleus and diaphragm muscles in mdx mice, indicating that OPG is not only a protector of bone but also skeletal muscles.

核因子κB受体激活因子（RANK）、核因子κB配体受体激活因子（RANKL）和骨保护素（OPG）通路的发现是骨生物学和疾病领域最重要的进展之一。RANK/RANKL/OPG是调控破骨细胞分化和功能的关键细胞因子系统。RANKL在成骨细胞中表达，而其受体RANK在破骨前细胞中表达。RANK/RANKL相互作用诱导多核成熟破骨细胞的形成，最终引起骨吸收。然而，第三个主角OPG也由成骨细胞产生，并对破骨前分化有抑制作用。OPG通过与RANKL结合，抑制RANKL/RANK相互作用和随后的破骨细胞生成。OPG缺失小鼠骨质疏松的事实证明了OPG在生理上的重要性。OPG还作为肿瘤坏死因子相关的诱导凋亡配体的诱饵受体，并通过阻断RANK/RANKL相互作用的促凋亡作用来提高细胞存活率。因此，OPG是一种非常有效的抗细胞吸收和抗细胞凋亡的药物。然而，我们最近在美国的出版物。j .分册。（2015）令人信服地表明，OPG- fc在mdx小鼠中完全恢复了快抽动指长伸肌的功能，并显著改善了慢抽动比目鱼肌和膈肌的功能，表明OPG不仅是骨骼的保护者，也是骨骼肌的保护者。