Intra-Articular Lactate Dehydrogenase A Inhibitor Oxamate Reduces Experimental Osteoarthritis and Nociception in Rats via Possible Alteration of Glycolysis-Related Protein Expression in Cartilage Tissue

Abstract

Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.

Andrographolide Ameliorates Inflammatory Changes Induced by D-Lactate in Bovine Fibroblast-like Synoviocytes

“…These findings suggest that metabolic reprogramming plays a pivotal role in the proinflammatory effect observed in bFLS induced by both D-lactate and TNFα. In addition, the intra-articular administration of oxamate, acting as an LDHA inhibitor, in a murine osteoarthritis model demonstrated reduced pain and inflammation, alongside an improvement in metabolic reprogramming [ 59 ]. Moreover, it has been demonstrated that knocking down HIF-1α in RA-FLS led to a reduction in LDHA and phosphofructokinase expression [ 57 ].…”

Glycolysis: an emerging regulator of osteoarthritis

“…It is supported that the glycolytic pathway or some of its key proteins can regulate chondrocyte apoptosis in the course of OA. The LDHA inhibitor oxalate has been shown to reduce chondrocyte apoptosis in articular cartilage of the experimental osteoarthritis rat model by possibly altering the expression of glycolysis-related proteins ( 154 ). Dexamethasone has been found to increase ROS levels and inhibit monocarboxylate transporter 4 (MCT4), leading to apoptosis caused by lactate accumulation ( 136 ).…”