The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway

Abstract

Despite the high prevalence of osteoarthritis (OA) in older populations, disease-modifying OA drugs (DMOADs) are still lacking. This study was performed to investigate the effects and mechanisms of the small molecular drug salicin (SA) on OA progression. Primary rat chondrocytes were stimulated with TNF-α and treated with or without SA. Inflammatory factors, cartilage matrix degeneration markers, and cell proliferation and apoptosis markers were detected at the mRNA and protein levels. Cell proliferation and apoptosis were evaluated by EdU assays or flow cytometric analysis. RNA sequencing, molecular docking and drug affinity-responsive target stability analyses were used to clarify the mechanisms. The rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. We found that SA rescued TNF-α-induced degeneration of the cartilage matrix, inhibition of chondrocyte proliferation, and promotion of chondrocyte apoptosis. Mechanistically, SA directly binds to IRE1α and occupies the IRE1α phosphorylation site, preventing IRE1α phosphorylation and regulating IRE1α-mediated endoplasmic reticulum (ER) stress by IRE1α-IκBα-p65 signaling. Finally, intra-articular injection of SA-loaded lactic-co-glycolic acid (PLGA) ameliorated OA progression by inhibiting IRE1α-mediated ER stress in the OA model. In conclusion, SA alleviates OA by directly binding to the ER stress regulator IRE1α and inhibits IRE1α-mediated ER stress via IRE1α-IκBα-p65 signaling. Topical use of the small molecular drug SA shows potential to modify OA progression.

Osteoarthritis: Natural bark extract could limit disease progression

Salicin, a small molecule extracted from willow bark, could provide a safe, effective injectable treatment for osteoarthritis, particularly in the early stages of the disease. Osteoarthritis is driven by stress in the intracellular endoplasmic reticulum (ER), which results in chronic inflammation and death of chondrocytes, the cells involved in cartilage formation. Salicin, which is metabolized into salicylic acid after oral ingestion, already forms the basis of aspirin and other anti-inflammatory pain relievers, but the exact mechanisms of its action in osteoarthritis are unclear. In experiments on cell cultures and rats, Junyi Liao, Wei Huang and co-workers at Chongqing Medical University, Chongqing, China, showed how salicin binds directly to a protein involved in promoting ER stress, blocking its activity. This in turn prevented the degeneration of the cartilage matrix and boosted levels of healthy chondrocytes.