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.
Highlights
Transforming growth factor beta (TGFβ) is a key profibrogenic cytokine in multiple organs including skeletal muscle and heart[12,13,14]
We established that selective depletion of αv integrins on PDGFRβ+ cells protects mice from fibrosis in both these muscle types, and αv integrin depletion on PDGFRβ+ cells had no adverse effects on skeletal muscle regeneration
We found that Pdgfrb-Cre effectively targeted quiescent PDGFRβ+ cells and activated myofibroblasts in both skeletal and cardiac muscle
Summary
Transforming growth factor beta (TGFβ) is a key profibrogenic cytokine in multiple organs including skeletal muscle and heart[12,13,14]. The molecular pathways regulating local activation of TGFβ at the site of injury and fibrogenesis represent attractive targets for novel anti-fibrotic therapies. We exploited a recently developed genetic system (Pdgfrb-Cre) in mice to identify molecular mechanisms driving skeletal and cardiac muscle fibrosis, and focussed on the integrin αv subunit because of the aforementioned role of αv integrins in activating latent TGFβ, a central mediator of fibrosis. In addition to a genetic approach, we investigated the utility of a small molecule inhibitor of αv integrins (CWHM 12) as a potential anti-fibrotic therapy for both skeletal and cardiac muscle fibrosis. Treatment with CWHM 12 attenuates fibrosis in both skeletal muscle and heart, even after the fibrotic process is established
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