TRPV4 mediates cell damage induced by hyperphysiological compression and regulates COX2/PGE2 in intervertebral discs

Elena Cambria; Sally Heusser; Ariane C Scheuren; Wai Kit Tam; Agnieszka A Karol; Wolfgang Hitzl; Victor Y Leung; Ralph Müller; Stephen J Ferguson; Karin Wuertz-Kozak

doi:10.1002/jsp2.1149

TRPV4 mediates cell damage induced by hyperphysiological compression and regulates COX2/PGE2 in intervertebral discs

JOR Spine. 2021 May 6;4(3):e1149. doi: 10.1002/jsp2.1149. eCollection 2021 Sep.

Authors

Affiliations

¹ Institute for Biomechanics ETH Zurich Zurich Switzerland.
² Department of Orthopaedics and Traumatology The University of Hong Kong Pokfulam Hong Kong.
³ Musculoskeletal Research Unit (MSRU), Department of Molecular Mechanisms of Disease (DMMD), Vetsuisse Faculty University of Zurich Zurich Switzerland.
⁴ Research Office (Biostatistics) Paracelsus Medical University Salzburg Austria.
⁵ Department of Ophthalmology and Optometry Paracelsus Medical University Salzburg Austria.
⁶ Research Program Experimental Ophthalmology and Glaucoma Research Paracelsus Medical University Salzburg Austria.
⁷ Department of Biomedical Engineering Rochester Institute of Technology Rochester New York USA.
⁸ Spine Center, Schön Klinik München Harlaching Academic Teaching Hospital and Spine Research Institute of the Paracelsus Private Medical University Salzburg (Austria) Munich Germany.

Abstract

Background: Aberrant mechanical loading of the spine causes intervertebral disc (IVD) degeneration and low back pain. Current therapies do not target the mediators of the underlying mechanosensing and mechanotransduction pathways, as these are poorly understood. This study investigated the role of the mechanosensitive transient receptor potential vanilloid 4 (TRPV4) ion channel in dynamic compression of bovine nucleus pulposus (NP) cells in vitro and mouse IVDs in vivo.

Methods: Degenerative changes and the expression of the inflammatory mediator cyclooxygenase 2 (COX2) were examined histologically in the IVDs of mouse tails that were dynamically compressed at a short repetitive hyperphysiological regime (vs sham). Bovine NP cells embedded in an agarose-collagen hydrogel were dynamically compressed at a hyperphysiological regime in the presence or absence of the selective TRPV4 antagonist GSK2193874. Lactate dehydrogenase (LDH) and prostaglandin E2 (PGE2) release, as well as phosphorylation of mitogen-activated protein kinases (MAPKs), were analyzed. Degenerative changes and COX2 expression were further evaluated in the IVDs of trpv4-deficient mice (vs wild-type; WT).

Results: Dynamic compression caused IVD degeneration in vivo as previously shown but did not affect COX2 expression. Dynamic compression significantly augmented LDH and PGE2 releases in vitro, which were significantly reduced by TRPV4 inhibition. Moreover, TRPV4 inhibition during dynamic compression increased the activation of the extracellular signal-regulated kinases 1/2 (ERK) MAPK pathway by 3.13-fold compared to non-compressed samples. Trpv4-deficient mice displayed mild IVD degeneration and decreased COX2 expression compared to WT mice.

Conclusions: TRPV4 therefore regulates COX2/PGE2 and mediates cell damage induced by hyperphysiological dynamic compression, possibly via ERK. Targeted TRPV4 inhibition or knockdown might thus constitute promising therapeutic approaches to treat patients suffering from IVD pathologies caused by aberrant mechanical stress.

Keywords: dynamic compression; low back pain; mechanobiology; mechanosensing; mechanotransduction; transient receptor potential channels.