Inhibition of Integrin αvβ6 Activation of TGF-β Attenuates Tendinopathy

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-beta) activated by integrin alpha v beta 6 promotes tendinopathy in mice. Excessive active TGF-beta is found during tendinopathy progression, which led to tenocytes' phenotype transition to chondrocytes. Transgenic expression of active TGF-beta in tendons induced spontaneous tendinopathy, whereas systemic injection of a TGF-beta neutralizing antibody attenuated tendinopathy. Inducible knockout of the TGF-beta type 2 receptor gene (Tgfbr2) in tenocytes inhibited tendinopathy progression in mice. Moreover, it is found that integrin alpha v beta 6 induces TGF-beta activation in response to mechanical load in tendons. Conditional knockout of the integrin alpha v gene in tendons prevented tendinopathy in mice. The study suggests that integrin alpha v beta 6 activation of TGF-beta is the mechanism of tendinopathy, and that integrin alpha v beta 6 may be a therapeutic target in tendinopathy.