Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis

Intervertebral disc (IVD) degeneration is the leading cause of disability with no disease-modifying treatment. IVD degeneration is associated with instable mechanical loading in the spine, but little is known about how mechanical stress regulates nucleus notochordal (NC) cells to maintain IVD homeostasis. Here we report that mechanical stress can result in excessive integrin alpha(v)beta(6)-mediated activation of transforming growth factor beta (TGF beta), decreased NC cell vacuoles, and increased matrix proteoglycan production, and results in degenerative disc disease (DDD). Knockout of TGF beta type II receptor (T beta RII) or integrin alpha(v) in the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGF beta, and alpha(v)beta(6)-neutralizing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGF beta plays a critical role in mechanical signaling transduction to regulate IVD cell function and homeostasis. Manipulation of this signaling pathway may be a potential therapeutic target to modify DDD.