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.
This video aims to describe an endoscopic surgical approach for accessing difficult to reach pathology such as disc herniations after previous surgery. The relatively small size of endoscopic instruments facilitates significant freedom of movement inside the spinal canal. The authors have experience with interlaminar approaches for contralateral pathology such as disc herniations, recurrent disc herniations, spinal stenosis, and facet cysts. The advantages of starting from the opposite side of the canal in a revision situation include the ability to establish a clear plane between the dura and the borders of the canal and visualize the disc from a different angle than the index operation. Contralateral approaches to residual or recurrent herniations can be performed with an “over the top” technique, navigating dorsal to the thecal sac to reach the far side of the canal. In the associated video we demonstrate a novel technique, a contralateral transaxillary endoscopic approach to a recurrent disc herniation at the L5–S1 level in a young male collegiate wrestler. In our experience, we have found this particular approach to be useful in patients with an early take off of the S1 nerve root which creates a large axillary window. In several instances this technique has allowed us to inspect the area of the reherniation from both the axilla and over the top of the thecal sac. This particular patient has a large recurrence 2 years after an open microscopic hemilaminotomy and discectomy. In this instance, an approach was chosen that navigates dorsal to the S1 nerve root and ventral to the thecal sac, starting on the opposite side of the spinal canal from the herniation. This approach is described as a contralateral interlaminar transaxillary discectomy.
Proteoglycans through their sulfated glycosaminoglycans regulate cell-matrix signaling during tissue development, regeneration, and degeneration processes. Large extracellular proteoglycans such as aggrecan, versican, and perlecan are especially important for the structural integrity of the intervertebral disc and cartilage during development. In these tissues, proteoglycans are responsible for hydration, joint flexibility, and the absorption of mechanical loads. Loss or reduction of these molecules can lead to disc degeneration and skeletal dysplasia, evident from loss of disc height or defects in skeletal development respectively. In this review, we discuss the common proteoglycans found in the disc and cartilage and elaborate on various murine models and skeletal dysplasias in humans to highlight how their absence and/or aberrant expression causes accelerated disc degeneration and developmental defects.
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