Pyruvate Kinase M2 Modulates the Glycolysis of Chondrocyte and Extracellular Matrix in Osteoarthritis

Abstract

Pyruvate kinase M2 (PKM2) has been wildly verified to modulate glycolysis in tumor cells. However, the role of PKM2 on the glycolysis of osteoarthritis (OA) chondrocytes is still unclear. In present study, we investigate the function of PKM2 on OA chondrocyte glycolysis and the collagen matrix generation in vitro. Results showed that PKM2 was upregulated in OA chondrocytes compared with healthy control chondrocytes. In OA chondrocytes, ATP expression was lower compared with healthy control chondrocytes. Loss-of-function experiment showed that PKM2 knockdown mediated by lentivirus transfection could significantly suppress the glucose consumption and lactate secretion levels and decrease glucose transporter-1 (Glut-1), lactate dehydrogenase A (LDHA), and hypoxia inducible factor 1-alpha (HIF-1α), indicating the inhibition of PKM2 knockdown on glycolysis. Moreover, Cell Counting Kit-8 (CCK-8), flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay showed that PKM2 knockdown inhibited OA chondrocyte proliferation and promoted the apoptosis. Western blot and immunocytochemical staining showed that PKM2 knockdown downregulated the expression levels of COL2A1 and SOX-9. In summary, our results conclude that PKM2 modulates the glycolysis and extracellular matrix generation, providing the vital role of PKM2 on OA pathogenesis and a novel therapeutic target for OA.

LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis

“…We instead explored a paradigm by which inflammation and metabolism are reciprocally regulatory. IL-1β treatment caused metabolic reprogramming, mimicking the Warburg effect and expanding upon some previous reports studying chondrocyte metabolism [58][59][60] . Other gene expression sets from articular chondrocytes treated with IL-1β or OA chondrocytes also display similar alterations in metabolic enzyme expression 61,62 , confirming metabolic changes as a conserved aspect of OA.…”

Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

“…It is possible that CaMK4 affects glycolysis at additional points including the expression of glucose transporter 1 (GLUT-1), which was reportedly decreased in KN-93treated Th17-polarized cells from patients with SLE (30). Because silencing of PKM2 reduces the expression of GLUT-1 in a gastric cancer cell line (31) and chondrocytes (32), KN-93 may have reduced GLUT-1 expression through PKM2 in T cells.…”

Alteration of Metabolic Pathways in Osteoarthritis

“…Anaerobic glycolysis occurs at an increased rate in OA-affected chondrocytes [13] so that sufficient ATP can be generated for the repairing process because ATP acts on P2 receptors to promote ECM synthesis [10,14]. The pyruvate kinase M2 (PKM2) gene, which codes for the production of pyruvate kinase, was reported to be upregulated in OA-affected chondrocytes compared to healthy control chondrocytes [15], supporting this. Thus, any alteration of glucose concentration and its distribution between ECM and inside chondrocytes could have an influence on articular cartilage maintenance and repair.…”