αv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis

Authors: Iain R. Murray, Zaniah González, Johanna L. Baily, Ross Dobie, Robert Wallace, Alison C. MacKinnon, James R. Smith, Stephen N. Greenhalgh, Alexandra Thompson, Kylie P. Conroy, David W. Griggs, Peter Ruminski, Gillian A. Gray, Manvendra K. Singh, Mary Ann Campbell, Timothy J. Kendall, J. Dai, Yong Li, John P. Iredale, Hamish Simpson, Johnny Huard, Bruno Péault, Neil C. Henderson - Nature Communications 2017 cited by 102

Abstract 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.