Combined therapeutic effects of Renshenguben and swimming on knee osteoarthritis associated with the gut-joint axis and HDAC3/PPAR-γ signaling pathway.

BACKGROUND: Knee osteoarthritis (KOA) is a chronic degenerative joint disease characterized by cartilage destruction, subchondral bone remodeling, and inflammation. Gut microbiota dysbiosis and aberrant HDAC3/PPAR-γ signaling contribute to KOA progression. This study investigated the therapeutic effects of Renshenguben (RSGB) combined with swimming exercise in monosodium iodoacetate (MIA)-induced KOA and explored the underlying mechanisms. METHODS: Forty-five male Sprague-Dawley (SD) rats were randomly divided into Control, MIA, RSGB, Swimming, and Swimming+RSGB groups. KOA was induced by intra-articular MIA injection. RSGB was administered orally, and swimming exercise was performed for 4 weeks. Knee swelling, mechanical pain threshold, and motor performance were assessed. Serum inflammatory cytokines, cartilage degradation markers, and gut barrier indicators were measured by ELISA. Cartilage histology, immunohistochemistry, micro-computed tomography, qPCR, and western blot analyses were performed to evaluate joint pathology and HDAC3/PPAR-γ expression. Gut microbiota composition was analyzed using 16S rRNA gene sequencing. RESULTS: MIA induced joint inflammation, pain hypersensitivity, motor dysfunction, elevated CRP, COMP, MMP-1, MMP-13, TNF-α, IL-1β, NF-κB, DAO, and LPS, and decreased IL-10. RSGB or swimming alone partially alleviated these changes, while combined treatment showed the most pronounced improvements. Combined treatment preserved cartilage and subchondral bone, suppressed HDAC3, restored PPAR-γ expression. Additionally, KOA-associated gut dysbiosis was characterized by reduced microbial diversity and depletion of SCFA-producing bacteria, which was significantly reversed by combined treatment. CONCLUSION: RSGB combined with swimming exerts enhanced protective effects in KOA by reducing inflammation, improving gut barrier function, restoring microbiota homeostasis, and regulating the HDAC3/PPAR-γ axis, offering a promising integrative therapeutic strategy.