Inhibition of Integrin αvβ6 Activation of TGF-β Attenuates Tendinopathy

Abstract

Tendinopathy is a common tendon disorder that causes pain and impairs function. It is the most common reason for consultation with musculoskeletal specialists. The available therapies for tendinopathy are limited in number and efficacy and have unclear cellular and molecular mechanisms. Here it is shown that transforming growth factor-beta (TGF-β) activated by integrin αvβ6 promotes tendinopathy in mice. Excessive active TGF-β is found during tendinopathy progression, which led to tenocytes’ phenotype transition to chondrocytes. Transgenic expression of active TGF-β in tendons induced spontaneous tendinopathy, whereas systemic injection of a TGF-β neutralizing antibody attenuated tendinopathy. Inducible knockout of the TGF-β type 2 receptor gene (Tgfbr2) in tenocytes inhibited tendinopathy progression in mice. Moreover, it is found that integrin αvβ6 induces TGF-β activation in response to mechanical load in tendons. Conditional knockout of the integrin αv gene in tendons prevented tendinopathy in mice. The study suggests that integrin αvβ6 activation of TGF-β is the mechanism of tendinopathy, and that integrin αvβ6 may be a therapeutic target in tendinopathy.