Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis

Abstract

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 α_vβ₆-mediated activation of transforming growth factor beta (TGFβ), decreased NC cell vacuoles, and increased matrix proteoglycan production, and results in degenerative disc disease (DDD). Knockout of TGFβ type II receptor (TβRII) or integrin α_v in the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGFβ, and α_vβ₆-neutralizing antibodies attenuated IVD degeneration. Thus, integrin-mediated activation of TGFβ 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.

Spinal health: Halting disc degeneration

Treatments targeting a signalling molecule may help to prevent intervertebral disk (IVD) degeneration. As IVDs lose water and shrink, they become ineffective cushions, leading to back pain. This degeneration is a leading cause of disability, and no effective treatments are currently available. Unstable loading of spinal disks is known to be involved, but little is known about the underlying molecular mechanisms. Xu Cao at Johns Hopkins University in Maryland and an international team of coworkers investigated the cell-level events leading to IVD degeneration using different rodent models. They found that unstable loading led to high levels of the signalling molecule transforming growth factor beta (TGFβ), accelerating changes in disk cells and inducing IVD degeneration. Administration of an antibody reduced TGFβ levels and slowed deterioration, suggesting a potential therapeutic target for treatment of IVD degeneration.

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