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.