Histone H3K18 lactylation: An exercise-induced epigenetic mechanism that inhibits osteoclast activity and protects against osteoporosis

Objective Osteoclasts, through their excessive production, are the primary cause of postmenopausal osteoporosis. However, the influence of metabolism on osteoclastogenesis remains poorly understood. This study reveals that protein lactylation plays a critical role in osteoclast differentiation. Methods The ovariectomized (OVX) mouse model was used to investigate osteoporosis by examining glycolysis and lactate levels during osteoclast differentiation. Bone resorption was assessed through histomorphometric analysis. The effects of elevating lactate levels were tested both endogenously via exercise and exogenously through sodium lactate (NaLac) administration. Protein lactylation, focusing on histone modifications, was analyzed, and key osteoclastogenesis genes, including cathepsin K ( Ctsk ), matrix metalloproteinase 9 ( Mmp9 ), and matrix metalloproteinase 12 ( Mmp12 ), were quantified. The enzymes responsible for lactylation and delactylation were identified through cleavage under targets and tagmentation (CUT&Tag) and RNA-Seq analyses. Results Our findings showed that glycolysis and lactate levels were reduced during osteoclast differentiation in the OVX model, despite increased bone resorption. Elevating lactate through exercise or sodium lactate supplementation increased protein lactylation and mitigated OVX-induced bone loss. Mechanistically, lactate enhanced histone H3 lysine-18 lactylation (H3K18la), which suppressed osteoclast differentiation by downregulating key osteoclastogenesis genes like Ctsk, Mmp9 , and Mmp12 . Alanyl-tRNA synthetase 1 (AARS1) was identified as the lactylation “writer” that mediates H3K18la, with sirtuin 6 (SIRT6) acting as an “eraser” in a regulatory circuit. Conclusions Lactate suppresses osteoclast differentiation and alleviates osteoporosis through histone H3K18 lactylation, which downregulates osteoclastogenic genes including Ctsk, Mmp9 , and Mmp12 . The dynamic regulation of H3K18la involves AARS1 as the lactylation “writer”and SIRT6 as an “eraser”. The translational potential of this article This study reveals an epigenetic mechanism by which lactate regulates osteoclast function and suggests that exercise-induced lactate elevation or lactate supplementation may represent a viable therapeutic strategy for postmenopausal osteoporosis.