RT Journal Article
SR Electronic
T1 Modulation of TRPV4 Protects against Degeneration Induced by Sustained Loading and Promotes Matrix Synthesis in the Intervertebral Disc
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.18.516994
DO 10.1101/2022.11.18.516994
A1 Garrett W.D. Easson
A1 Alireza Savadipour
A1 Akila Anandarajah
A1 Leanne E. Iannucci
A1 Spencer P. Lake
A1 Farshid Guilak
A1 Simon Y. Tang
YR 2022
UL http://biorxiv.org/content/early/2022/11/18/2022.11.18.516994.abstract
AB While it is well-known that mechanical signals can either promote or disrupt intervertebral disc (IVD) homeostasis, the molecular mechanisms for transducing mechanical stimuli are not fully understood. The transient receptor potential vanilloid 4 (TRPV4) ion channel activated in isolated IVD cells initiates extracellular matrix (ECM) gene expression, while TRPV4 ablation reduces cytokine production in response to circumferential stretching. However, the role of TRPV4 on ECM maintenance during tissue-level mechanical loading remains unknown. Using an organ culture model, we modulated TRPV4 function over both short-(hours) and long-term (days) and evaluated IVDs’ response. Activating TRPV4 with the agonist GSK101 resulted in a Ca2+ flux propagating across the cells within the IVD. NF-κB signaling in the IVD peaked at 6 hours following TRPV4 activation that subsequently resulted in higher IL-6 production at 7 days. These cellular responses were concomitant with the accumulation of glycosaminoglycans and increased hydration in the nucleus pulposus that culminated in higher stiffness of the IVD. Sustained compressive loading of the IVD resulted in elevated NF-κB activity, IL-6 and VEGF-A production, and degenerative changes to the ECM. TRPV4 inhibition using GSK205 during loading mitigated the changes in inflammatory cytokines, protected against IVD degeneration, and but could not prevent ECM disorganization due to mechanical damage in the annulus fibrosus. These results indicate TRPV4 plays an important role in both short-and long-term adaptations of the IVD to mechanical loading. The modulation of TRPV4 may be a possible therapeutic for preventing load-induced IVD degeneration.Competing Interest StatementThe authors have declared no competing interest.