Glycolytic Metabolite 3-Phosphoglycerate Induced by Inflammation Inhibits Chondrocyte Survival

Abstract

The reduction of chondrocytes is an important pathological manifestation in the cartilage degeneration, and the abnormal metabolism of chondrocytes triggered by inflammation is the key reason for the inhibition of chondrocyte survival. The enhancement of glycolysis is an important feature of chondrocyte metabolism in inflammatory environments, but the effects of metabolic enzymes and metabolites on chondrocyte survival in this process are still unclear. In this study, we used transcriptomics to analyze the expression of glycolytic metabolic enzymes in condylar chondrocytes under inflammatory environments (IL-1β, 10 ng/mL) and identified phosphoglycerate kinase 1 (PGK1), the metabolic enzyme with the most significant increase in glycolysis, as well as improving the condylar chondrocytes survival and cartilage degeneration after inhibiting PGK1 activity. Subsequently, in metabolomics studies, we found that 3-phosphoglycerate (3-PGA), a direct metabolite of PGK1, increased significantly, and it was the most significantly increased among all detectable and labeled carbohydrate-related metabolites. Furthermore, condylar chondrocytes showed obvious survival inhibition in the presence of increased 3-PGA. Finally, we screened out the downstream molecule CXCL10 through transcriptomics-based joint analysis and computer algorithm selection. In summary, this study used transcriptomics and metabolomics, combined with cellular function and histological examination, to identify and validate that the metabolite of PGK1, 3-PGA, accumulates in the condylar chondrocytes in inflammatory environment, leading to significant inhibition of their survival. It specifically elucidates the molecular mechanism of enhanced glycolysis by which inflammation leads to inhibition of condylar chondrocytes survival, providing theoretical basis for understanding condylar cartilage degeneration from a metabolic perspective.