Investigating the Role of TRPV4 as a Mechanoreceptor in the Intervertebral Disc

Taylor Dominick Spence Shelton, Western University

Abstract

Transient Receptor Potential Cation Channel Subfamily V Member 4 (TRPV4) is a cell membrane Ca²⁺ channel that regulates intracellular calcium levels in response to mechanical stimuli. Recent studies have demonstrated that TRPV4 is required for the induction of extracellular gene expression in murine intervertebral disc (IVD) cells in response to mechanical load. We investigated the role of TRPV4 in age associated IVD degeneration and spine development using novel knockout mice. Spine samples were harvested from Noto^Cre;Trpv4^fl/fl and WT mice at embryonic day 13.5 (E13.5) as well as postnatal day 1 and postnatal day 21 samples using histological analysis. Noto^Cre;Trpv4^fl/fl mice demonstrated no difference in IVD structure compared to WT mice at each of the observed timepoints. In Col2^Cre;Trpv4^fl/fl (Trpv4^-/-) mice used to asses age-associated disc degeneration, 24-month-old male Trpv4^-/-mice showed gross changes in IVD structure at the L4/5 and L5/6 spinal levels compared to WT. Conversely, in 24-month female mice TRPV4 loss appeared to have a protective effect against IVD degeneration. This suggests that the loss of TRPV4 within the IVD may have a sex-specific effect in age-associated disc degeneration. Furthermore, 24-month-old female WT mice demonstrated significantly increased Trpv4 gene expression compared to male WT mice of the same age. Gene expression analysis of 24-month-old male mice, demonstrated a trend of increased expression of inflammatory markers Mmp-13, IL-1beta and IL-6 in Trpv4^-/-samples compared to WT. Altogether, these results further support the role of TRPV4 as an important mechanoreceptor within the IVD, that contributes to the adaptive response of the disc to mechanical load.