Fig. 8.

Schematic representation of lactate-induced oxidative stress. Lactate induces the expression of MCTs and SMCTs in chondrocytes, and enters chondrocytes through them. Lactate increased NADPH levels by promoting shunting of glucose to the pentose phosphate pathway and up-regulates NOX4 expression via binding receptor HCAR1 to activate the PI3K/Akt signaling pathway, leading to elevated ROS and further induced impaired chondrocytes characterized by promoting expression of catabolic enzymes, reducing the synthesis of type II collagen, secreting inflammatory cytokines and chemokines, and causing hypertrophy and aging. OA, osteoarthritis; MCT, monocarboxylate transporter; SMCT, sodium-coupled monocarboxylate transporter; HCAR1, hydroxy-carboxylic acid receptor 1; NADP, nicotinamide adenine dinucleotide phosphate; NOX, NADPH oxidase; HK, hexokinase; Glucose-6-P, glucose-6-phosphate; G6PD, glucose-6-phosphate dehydrogenase; 2-DG, 2-deoxy-d-glucose; ROS, reactive oxygen species.