Pioglitazone Regulates Chondrocyte Metabolism and Attenuates Osteoarthritis by Activating Peroxisome Proliferator‐Activated Receptor Gamma

Osteoarthritis presents a significant clinical challenge due to its high prevalence and the resultant impairment of patients' motor function. Osteoarthritic chondrocytes are characterised by inflammation and metabolic disturbances. Pioglitazone, an agonist of peroxisome proliferator-activated receptor γ (PPAR-γ), has been demonstrated to exert anti-inflammatory effects across various diseases. This study aims to investigate the potential protective effects of Pioglitazone on osteoarthritic chondrocytes. An in vitro chondrocyte inflammation model was established utilising IL-1β. The impact of Pioglitazone on chondrocyte inflammation and extracellular matrix synthesis was evaluated through enzyme-linked immunosorbent assay, immunofluorescence staining and Alcian blue staining. The affinity of Pioglitazone for PPAR-γ was investigated using molecular docking techniques. Alterations in chondrocyte glycolysis and oxidative phosphorylation were examined using the Seahorse XF Analyser, and the influence of Pioglitazone on glucose uptake and the mitochondrial electron transport chain was further analysed. Pioglitazone was gavaged in a mouse OA model established by anterior cruciate ligament transection to evaluate the therapeutic efficacy of Pioglitazone. Our findings indicate that Pioglitazone mitigates chondrocyte inflammation and osteoarthritis in murine models by inhibiting the expression of inflammatory mediators such as TNF-α, IL-6 and PGE2, and by preventing the degradation of aggrecan and collagen II. Furthermore, Pioglitazone significantly upregulated the expression of glucose transporter 1 and stabilised the mitochondrial proton delivery chain in a PPAR-γ-dependent manner, thereby enhancing chondrocyte glucose uptake, glycolysis, and oxidative phosphorylation. These effects were partially reversed by the PPAR-γ antagonist GW9662. Pioglitazone can confer chondroprotective benefits in osteoarthritis by activating PPAR-γ.