MEF2A/KMT2D/H3K4me3/LOX axis promotes osteoclast differentiation by increasing autophagic flux and participates in LPS-induced osteolysis

Overactivation of osteoclasts represents the core pathological mechanism driving bone destruction and pathological osteolysis, yet safe and effective targeted therapeutic strategies remain lacking in clinical settings. Lysyl Oxidase (LOX), an extracellular matrix-modifying enzyme, has been linked to osteoclast differentiation, but its precise regulatory role and molecular basis remain poorly defined. This study aimed to explore the function of LOX in osteoclast differentiation and elucidate the underlying mechanisms. We observed that LOX expression gradually increased during osteoclastogenesis, accompanied by enhanced autophagic flux. Knockdown of LOX markedly suppressed osteoclast formation and autophagic activity, whereas overexpression of LOX exerted the opposite effects. Mechanistic studies revealed that combined treatment with si-LOX and the Autophagy inhibitor 3-methyladenine further reduced the expression of key osteoclast-related proteins, while the Autophagy activator rapamycin partially reversed these inhibitory effects. Epigenetic analysis showed that the methyltransferase KMT2D was upregulated during osteoclast differentiation, accompanied by significantly increased H3K4me3 modification at the LOX promoter. Manipulating KMT2D expression correspondingly altered H3K4me3 enrichment and LOX transcription. Moreover, KMT2D interacted with transcription factor MEF2A and was recruited to the LOX promoter, thereby mediating LOX transcriptional activation. In vivo, local injection of LV-shLOX lentivirus effectively attenuated LPS-induced mouse calvarial osteolysis. Collectively, our results demonstrate that LOX promotes osteoclast differentiation by enhancing autophagic flux, which is transcriptionally upregulated via the MEF2A/KMT2D/H3K4me3 axis. LOX may represent a promising therapeutic target for osteolytic bone disorders.