Department of Trauma and Orthopaedics, University of Edinburgh, Chancellors Building, Little France Campus, Edinburgh, EH16 4TJ, UK.
BHF Centre for Vascular Regeneration & MRC Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
Nat Commun. 2017 Oct 24;8(1):1118. doi: 10.1038/s41467-017-01097-z.
Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRβ) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRβ cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRβ cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFβ activation in primary human skeletal muscle and cardiac PDGFRβ cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses.
表达血小板衍生生长因子受体 β (PDGFRβ) 的间质细胞已知在肝和肾等器官的纤维化中起重要作用。在这里，我们表明 PDGFRβ 细胞通过依赖于 αv 整联蛋白的机制促进骨骼肌和心肌纤维化。在 PDGFRβ 细胞中耗尽 αv 整联蛋白的小鼠可防止心脏毒素和撕裂伤诱导的骨骼肌纤维化以及血管紧张素 II 诱导的心脏纤维化。此外，αv 整联蛋白小分子抑制剂可减轻两种骨骼肌和心肌中已建立的纤维化，甚至改善骨骼肌功能。αv 整联蛋白阻断还可减少原代人骨骼肌和心脏 PDGFRβ 细胞中 TGFβ 的激活，表明 αv 整联蛋白抑制剂可能对广泛的肌肉纤维化的治疗和预防有效。
