The effects of intra-articular oxamate on anterior cruciate ligament transection-induced experimental osteoarthritic rats

Abstract

Background: Osteoarthritis (OA) is the most common form of joint disorder and arthritis worldwide. Joint pain and dysfunction are associated with this multifactorial disease characterized by the gradual degeneration of articular cartilage. The metabolic reprogramming of osteoarthritic chondrocytes to glycolysis instead of oxidative phosphorylation results in reduced ATP and lactate accumulation. When the glycolytic metabolite pyruvate is converted into lactate by lactate dehydrogenase A (LDHA), cartilage degeneration occurs. In the present study, we examined the chondroprotective effects of the LDHA inhibitor, oxamate on experimental OA rats. Methods: Anterior cruciate ligament transection (ACLT)-induced ACLT-rats received an intraarticular (IA) injection of oxamate once a week for 5 weeks from the 10th to 14th after surgery. Animals were divided into four groups as follows: Sham, ACLT, ACLT + oxamate (0.25mg/kg), and ACLT + oxamate (2.5mg/kg). The results showed that an IA injection of oxamate significantly reduced weight-bearing defects and knee swelling in ACLT-rats. Results: Histopathological analyses showed that oxamate caused significantly less cartilage degeneration than ACLT alone. Moreover, IA oxamate exerts hypertrophic effects in the chondrocyte of articular cartilage by inhibiting glucose-transporter 1, glucose-transporter 3, pyruvate kinase, LDHA, pyruvate dehydrogenase kinase 1, and pyruvate dehydrogenase kinase 2. Terminal deoxynucleotidyl transferase dUTP nick end labeling revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Conclusions: We propose that oxamate is beneficial for patients with OA and is associated with regulating glycolysis-related protein expression. In future clinical applications, our findings will provide new insights of LHDA inhibitor, oxamate into delaying strategies for OA progression.