title: 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 αvβ6-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 αvin the NC cells inhibited functional activity of postnatal NC cells and also resulted in DDD under mechanical loading. Administration of RGD peptide, TGFβ, and αvβ6-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.
authors.affiliation: 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.
authors.forename: Qin
authors.initials: Q
authors.lastname: Bian
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Jain
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA; Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Crane
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Khaled
authors.initials: K
authors.lastname: Kebaish
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
authors.affiliation: Department of Biomedical Engineering, Columbia University , NY, USA.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Biomedical Engineering, Columbia University , NY, USA.
authors.forename: X
authors.initials: X
authors.lastname: Edward Guo
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Sponseller
authors.affiliation: Departments of Physiology and Pharmacology, University of Western Ontario , London, Canada.
authors.forename: Cheryle A
authors.initials: CA
authors.lastname: Séguin
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Lee H
authors.initials: LH
authors.lastname: Riley
authors.affiliation: Institute of Spine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine , Shanghai, PR China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University , Baltimore, MD, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao