Glucocorticoid receptor represses the LGR4 gene by binding to the nGRE sequence and recruiting HDAC4 in mice...

The glucocorticoid receptor (GR) is a ligand-activated transcriptional regulator that translocates from the cytoplasm to the nucleus and modulates gene expression by binding DNA elements and recruiting coregulators. Synthetic glucocorticoids promote osteoclast overactivation, but the transcriptional mechanisms in osteoclast precursors remain incompletely defined. In glucocorticoid-stimulated monocytes, the leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4), a gene inhibiting osteoclastogenesis, is significantly repressed and osteoclast differentiation genes are upregulated. In our previous work, we found that classical monocytes contribute to osteoclastogenesis and display low expression of LGR4. However, the underlying mechanism has not been fully elucidated. In this study, we show that the glucocorticoid receptor occupies a negative glucocorticoid response element (nGRE) within the LGR4 promoter and recruits histone deacetylase 4 (HDAC4), thereby repressing LGR4 transcription and enhancing osteoclast differentiation programs. These findings suggest that disrupting GR-HDAC4-mediated repression of LGR4 may provide a strategy to mitigate glucocorticoid-enhanced osteoclastogenesis.