Lactate regulates osteoclastogenesis via H3k18la in osteoarthritis

Osteoarthritis (OA), characterized by articular cartilage degeneration and subchondral bone remodeling, is a notable cause of disability globally. The present study aimed to explore the role and mechanism of histone H3 lysine 18 lactylation (H3K18la) in OA osteoclast differentiation and verify the therapeutic potential of targeting this pathway. Using a mouse OA model (anterior cruciate ligament transection), RAW264.7 cell experiments, oxmacid‑mediated lactate inhibition and cleavage under targets and tagmentation to map genomic targets, the present study demonstrated elevated H3K18la in OA joint osteoclasts, associated with reduced bone mineral density and aggravated subchondral bone destruction. Analysis of TRAP and lactate indicated that RANKL‑induced osteoclast differentiation increased lactate production, enhancing H3K18la; oxmacid inhibited both of these processes. H3K18la was enriched at the acid phosphatase 5 promoter and directly promoted its transcription. Local oxmacid injection in OA mice decreased osteoclast numbers and alleviated subchondral bone loss. Thus, H3K18la was a key metabolic‑epigenetic mediator linking glycolysis to osteoclast differentiation, representing a novel OA therapeutic target.