Myricetin Restores Autophagy to Attenuate Lumbar Intervertebral Disk Degeneration Via Negative Regulation of the JAK2/STAT3 Pathway.

Autophagy is a critical player in lumbar intervertebral disk degeneration (IDD), and autophagy activation has been suggested to prevent the apoptosis of nucleus pulposus cells (NPCs). Myricetin has anti-cancer, anti-inflammatory, and antioxidant potentials and can activate autophagy. Thus, this study focused on the roles and mechanisms of myricetin in IDD. A puncture-induced rat IDD model was established and intraperitoneally injected with 20-mg/kg/day myricetin. Histopathological changes of intervertebral disks (IVDs) were assessed by hematoxylin and eosin staining and Safranin O/Fast Green staining. The isolated NPCs from IVDs of healthy rats were stimulated with IL-1ß to mimic IDD-like conditions. The roles of myricetin in cell apoptosis, extracellular matrix (ECM) degradation, autophagy repression, and the JAK2/STAT3 pathway activation were examined by cell counting kit-8, flow cytometry, western blotting, real-time quantitative polymerase chain reaction, and immunofluorescence staining. Myricetin treatment attenuated the apoptosis and ECM degradation, and enhanced autophagy in the IL-1ß-treated NPCs, whereas the myricetin-mediated protection was limited by autophagy inhibition. Mechanistically, myricetin activated autophagy through blocking the JAK2/STAT3 signaling. In vivo experiments revealed that intraperitoneal injection of myricetin activated NPC autophagy to relieve puncture injury in rats. Myricetin prevents IDD by attenuating NPC apoptosis and ECM degradation through blocking the JAK2/STAT3 pathway to enhance autophagy.

Myricetin Protects Against Rat Intervertebral Disc Degeneration Partly Through the Nrf2/HO-1/NF-κB Signaling Pathway.

Intervertebral disc (IVD) degeneration (IDD) is a prevalent musculoskeletal disorder. Nucleus pulposus cells (NPCs) play a significant role in the normal functioning of the IVD. Myricetin is an agent that exerts anti-inflammatory and antioxidant effects in various pathological conditions. Here, we investigated the ameliorative effects of myricetin on the IVD degeneration. NPCs were obtained from the IVD of rats, and were treated with myricetin (0, 5, 10, 15, 20 µM) for 24 h before 20 ng/mL IL-1ß stimulation. RT-qPCR, western blotting, and ELISA were applied to evaluate the levels of inflammatory factors (iNOS, COX-2, TNF-α, IL-6, PGE2, and Nitrite) and extracellular matrix (ECM)-associated components (MMP13, ADAMTS-5, aggrecan, and collagen II) in NPCs. Activation status of related signaling pathways (NF-κB and Nrf2) was determined using western blotting and immunofluorescence staining. Experimental rat models of IDD were established using a needle puncture method. Myricetin (20 mg/kg) was administrated intraperitoneally, and the degeneration was evaluated using histopathological analysis. Myricetin treatment attenuated the IL-1ß-induced production of inflammatory factors in NPCs. Downregulation of aggrecan and collagen II as well as upregulation of MMP-13 and ADAMTS-5 in NPCs caused by IL-1ß was reversed by myricetin treatment. Mechanistically, myricetin blocked NF-κB signaling by activation of Nrf2 in IL-1ß-stimulated NPCs. Moreover, inhibition of Nrf2 reversed the protective effects of myricetin in NPCs. The in vivo experiments showed that myricetin ameliorated the IDD progression in rats. The present work suggests that Nrf2 is involved in the pathogenesis of IDD and shows the protective effects as well as the underlying mechanism of myricetin on Nrf2 activation in NPCs.