Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice
Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice
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DOI：
10.1038/nm.3917
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发表时间：
2015-09-01
期刊：
影响因子：
82.9
通讯作者：
Pap, Thomas
中科院分区：
文献类型：
--
作者：
Dankbar, Berno;Fennen, Michelle;Pap, Thomas
肌生长抑制素（也称为生长和分化因子8）是转化生长因子-β（TGF-β）家族的分泌成员，其主要在骨骼肌中表达，骨骼肌也是其主要靶组织。小鼠中肌肉生长抑制素基因（MSTs）的缺失导致肌肉肥大，动物研究支持肌肉生长抑制素是肌肉生长和再生的负调节剂的概念（1-5）。然而，肌肉生长抑制素缺乏也增加骨形成，主要是通过对骨的负荷相关影响（6-11）。在这里，我们报告了一个以前未知的直接作用，肌肉生长抑制素在破骨细胞和关节骨的类风湿性关节炎（RA）进行性损失。我们证明肌生长抑制素在RA受试者和人肿瘤坏死因子（TNF）-α转基因（hTNFtg）小鼠（人RA模型）的滑膜组织中高度表达（12）。肌生长抑制素强烈加速核因子κ B配体受体激活因子（RANKL）介导的破骨细胞依赖性活化T细胞核因子（NFATC 1）调节。肌生长抑制素缺乏或抗体介导的抑制导致hTNFtg小鼠关节炎严重程度的改善，主要表现为骨破坏较少。与hTNFtg小鼠中的这些作用一致，缺乏肌肉生长抑制素导致小鼠中K/BxN血清诱导的关节炎模型中握力增加和骨侵蚀减少。结果强烈表明，肌生长抑制素是一个有效的治疗靶点，干扰破骨细胞的形成和关节破坏的RA。
Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-beta (TGF-beta) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration(1-5). However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone(6-11). Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-alpha transgenic (hTNFtg) mice, a model for human RA(12). Myostatin strongly accelerates receptor activator of nuclear factor kappa B ligand (RANKL)-mediated osteoclas-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.