Rhapontigenin inhibits inflammation and senescence of chondrocytes from patients with osteoarthritis by targeting INHBA.

Abstract

OBJECTIVES: Rhapontigenin (RHAP), a natural small molecular stilbenoid extracted from Chinese herbal medicine Rhubarb, exhibits anti-inflammatory, antioxidant, antibacterial effects and protection on heart and nerve. However, its role in the treatment of osteoarthritis (OA) is unknown. Here, we investigated the role of RHAP in regulating functions of chondrocyte from patients with OA, and its therapeutic effect on animal model of OA. METHODS: Chondrocytes were obtained from tibial plateau cartilage in established OA patients. Chondrocyte viability was measured by CCK8 and the morphological changes was observed by Safranin O staining. Cell proliferation was assessed by EdU while apoptosis detected by flow cytometry. Gene expression was determined using quantitative RT-PCR. Protein expression was presented by western blotting or immunohistochemistry. Senescent chondrocytes were labeled by SA-β-gal staining. The target genes of RHAP were screened using RNA sequencing analysis. Monosodium Iodoacetate (MIA)-induced rat knee OA model was applied to evaluate the in vivo effect of RHAP. RESULTS: Treatment with RHAP increased the viability and proliferation of OA chondrocyte. RHAP treatment inhibited the expression of inflammatory cytokines (IL-6, IL-8, COX-2), suppressed extracellular matrix degradation (MMP1, MMP9, MMP13), promoted matrix protein synthesis and attenuated cell senescence in chondrocytes induced by IL-1β. Mechanistically, we identified INHBA as a novel targeting gene of RHAP in OA chondrocyte. RHAP inhibits IL-1β-induced inflammation and senescence by downregulating INHBA mediated phosphorylation of the AKT/FoxO1 signaling pathway. Interestingly, RHAP treatment alleviated the severity of arthritis and reduced chondrocytes INHBA expression in MIA rats. CONCLUSIONS: We demonstrated that RHAP treatment inhibits inflammation and senescence of OA chondrocytes via a reduction of INHBA expression and sequential activation of AKT/FOXO1 pathway. Our findings suggest that RHAP might control inflammation and degeneration of cartilage in OA, and be a potential therapeutic agent for OA.