Targeted disruption of PRC1.1 complex enhances bone remodeling

Polycomb repressive complexes (PRCs) are pivotal epigenetic regulators preserving cell identity by restricting the transcription responsiveness to sub-threshold levels of extracellular signals. Their roles in osteoblast function and bone formation remain largely unexplored. Here in aging osteoblasts, we observed a selective activation of PRC1.1 complex, with KDM2B acting as a chromatin-binding factor and BCOR and PCGF1 serving as essential catalytic partners for histone H2A monoubiquitylation (H2AK119ub1). Using genetic models, we found that osteoblast-specific KDM2B inactivation significantly enhances bone remodeling under steady-state conditions and in scenarios of bone loss. This enhancement is attributed to H2AK119ub1 downregulation which leads to the derepression of Wnt signaling. Furthermore, we developed a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Notably, iBP promotes bone formation in mouse models of bone loss. Therefore, our findings suggest that targeting PRC1.1 augments cellular responses to Wnt signaling and may offer a promising strategy to counteract bone deterioration.