Lactate and Acidification: Emerging Metabolic Regulators of Osteoarthritis

Abstract

Osteoarthritis (OA) is a prevalent degenerative and inflammatory disease posing a significant financial and medical burden on patients and society. Lactic acid, the terminal metabolite of glycolysis, is recognized as a pivotal signaling molecule governing diverse physiological and pathological processes, particularly in cancer and inflammatory diseases. Emerging evidence suggests that metabolic disorders are closely associated with OA, which may provide a metabolic lens for further exploring its mechanisms. Glycolytic reprogramming is now recognized as a hallmark of OA, leading to the pronounced accumulation of lactic acid within the joint microenvironment. This review synthesizes current evidence to elucidate the role of lactic acid in OA pathogenesis. We summarize the mechanism of glycolytic reprogramming in chondrocytes and macrophages under pathological conditions. Furthermore, we demonstrate that lactic acid exacerbates cartilage degeneration while simultaneously promoting inflammation resolution. These dual roles are mediated by extracellular acidification, HCAR1, and lactylation. Given that duality, we suggest that redirecting lactate flux presents considerable potential as a therapeutic approach for the prevention and management of OA.

Keywords

Chondrocytes / Metabolic reprogramming / Osteoarthritis / Lactylation / Hydroxycarboxylic acid receptor 1 (HCAR1) / Macrophages / Extracellular acidification

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Funding

National Natural Science Foundation of China(82271425)

Jilin Province Health Science and Technology Capacity Enhancement Program(2025WS-KA017)

RIGHTS & PERMISSIONS

The Author(s), under exclusive licence to the Huazhong University of Science and Technology