Objective Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, has been implicated in intervertebral disc homeostasis; however, its role in autophagy regulation remains unclear. This study aimed to investigate whether agonist-induced TRPV4 activation promotes autophagy and extracellular matrix (ECM) synthesis in rat intervertebral discs.
Methods In vitro, rat nucleus pulposus (NP) cells were treated with the TRPV4 agonist (GSK1016790) under normal, serum-deprived, or interleukin-1β-stimulated conditions. Cell viability, intracellular Ca2+ influx, adenosine monophosphate-activated protein kinase/mammalian target of rapamycin (mTOR) (AMPK/mTOR) pathway, autophagy, ECM metabolism, apoptosis, and senescence were evaluated. In vivo, TRPV4 agonist was injected into the caudal discs subjected to temporary static compression, and disc changes were assessed by radiography, histomorphology, and immunofluorescence.
Results In vitro, agonist-induced TRPV4 activation rapidly increased intracellular Ca2+ influx and enhanced AMPK phosphorylation. A noncytotoxic concentration of the TRPV4 agonist (10 nM) was selected after dose-response testing. Under the inflammatory stress, TRPV4 agonist enhanced autophagy, promoted ECM synthesis, and suppressed apoptosis and senescence, leading to improved NP cell viability. In vivo, TRPV4 agonist treatment preserved radiographic disc height (p<0.01), reduced histomorphological degeneration (p<0.01), and increased expression of COL2A1, Brachyury, p-AMPK (phosphorylated AMPK), and autophagy markers (p<0.01) compared with controls.
Conclusion These findings demonstrated that TRPV4 activation promotes autophagy and ECM synthesis via the AMPK/mTOR pathway in rat discs and attenuates stress-induced degeneration, suggesting TRPV4 as a potential therapeutic target for disc degeneration.
The extracellular matrix (ECM) is a protein-and-carbohydrate meshwork that supports a variety of biological structures and processes, from tissue development and elasticity to the preservation of organ structures. ECM composition is different in each organ. It is a remarkably dynamic 3-dimensional structure that's constantly changing to maintain tissue homeostasis. This review aims to describe the involvement of ECM components in the remodeling process of spinal cord injury (SCI) and intervertebral disc degeneration (IVDD). Here, we have also described the current ECM-based therapeutic targets, which can be explored for ECM remodeling SCI is a neurological condition with intense influences resulting from a trauma inflicted on the spinal cord. SCI leads to damage to the intact ECM that leads to regeneration failure. IVDD mainly occurs due to aging and trauma. Various ECM components enable fragmentation of the disc and are thereby involved in disc degeneration. ECM manipulation can be used as an adjunct treatment in SCI and IVDD. Current treatment approaches for SCI and IVDD are conservative and unsatisfactory. Targeting ECM remodeling as an adjunct therapy may result in better disease outcomes.
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