Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis

Qin Bian; Lei Ma; Amit Jain; Janet L Crane; Khaled Kebaish; Mei Wan; Zhengdong Zhang; X Edward Guo; Paul D Sponseller; Cheryle A Séguin; Lee H Riley; Yongjun Wang; Xu Cao

doi:10.1038/boneres.2017.8

Mechanosignaling activation of TGFβ maintains intervertebral disc homeostasis

Bone Res. 2017 Mar 21:5:17008. doi: 10.1038/boneres.2017.8. eCollection 2017.

Authors

Qin Bian¹, Lei Ma², Amit Jain², Janet L Crane³, Khaled Kebaish², Mei Wan², Zhengdong Zhang⁴, X Edward Guo⁴, Paul D Sponseller², Cheryle A Séguin⁵, Lee H Riley², Yongjun Wang⁶, Xu Cao²

Affiliations

¹ Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA; Institute of Spine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, PR China.
² Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
³ Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA.
⁴ Department of Biomedical Engineering, Columbia University , NY, USA.
⁵ Departments of Physiology and Pharmacology, University of Western Ontario , London, Canada.
⁶ Institute of Spine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine , Shanghai, PR China.

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.

Grants and funding

K08 AR064833/AR/NIAMS NIH HHS/United States