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

This study investigated whether the mechanosensitive ion channel TRPV4 mediates deleterious cellular and inflammatory responses to hyperphysiological dynamic compression in intervertebral discs (IVDs). In vivo, mouse tail IVDs were subjected to short, repetitive dynamic compression (8 N,2 Hz,5 min,3x/week for 4 weeks), producing mild degenerative features by multichromatic FAST histology, while COX2 immunohistochemistry in this short loading paradigm did not show a clear compression-dependent change. In vitro, bovine nucleus pulposus (NP) cells were embedded in a matrix-mimicking agarose-collagen hydrogel and exposed to hyperphysiological dynamic compression, which increased LDH release (cell damage) and modestly increased PGE2 release at 48 h post-loading. Pharmacologic TRPV4 inhibition (GSK2193874) during loading significantly reduced compression-induced LDH and PGE2 release, implicating TRPV4 in transducing damaging compression. MAPK profiling indicated that TRPV4 inhibition during compression significantly increased ERK phosphorylation (p-ERK/ERK), consistent with a potential pro-survival signaling shift. Finally, trpv4-deficient mouse IVDs displayed mild degenerative changes and reduced COX2 expression versus wild-type, supporting a role for TRPV4 in IVD homeostasis and COX2/PGE2 regulation.