Targeted disruption of PRC1.1 complex enhances bone remodeling.

Liangyu Xing, Jinxin Xu, Meihan Gong, Yunzhi Liu, Xuanyuan Li, Lingyu Meng, Ruyue Du, Ying Zhou, Zhaoguang Ouyang, Xu Liu, Shaofei Tao, Yuxin Cao, Chunyi Liu, Feng Gao, Ruohui Han, Hui Shen, Yan Dong, Yong Xu, Tao Li, He Chen, Yingying Zhao, Baoyou Fan, Lei Sui, Shiqing Feng, Jinsong Liu, Dayong Liu, Xudong Wu

State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Endodontics, Tianjin Medical University School and Hospital of Stomatology & Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, Tianjin, China.State Key Laboratory of Experimental Hematology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory of Medical Epigenetics, Department of Endodontics, Tianjin Medical University School and Hospital of Stomatology & Tianjin Key Laboratory of Oral Soft and Hard Tissues Restoration and Regeneration, Tianjin Medical University, Tianjin, China. · pubmed

Paper

Abstract

Polycomb repressive complexes (PRCs) are pivotal epigenetic regulators that preserve cell identity by restricting transcription responses to sub-threshold extracellular signals. Their roles in osteoblast function and bone formation remain unclear. Here in aging osteoblasts, we found marked activation of PRC1.1 complex, with KDM2B acting as a chromatin-binding factor and BCOR and PCGF1 enabling histone H2A monoubiquitylation (H2AK119ub1). 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 and subsequent Wnt signaling derepression. Furthermore, we developed a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Notably, iBP administration promotes bone formation in mouse models of bone loss. Therefore, our findings identify PRC1.1 as a critical epigenetic brake on bone formation and demonstrate that therapeutic targeting of this complex enhances Wnt pathway activation, offering a promising strategy against skeletal deterioration.

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Research summary

Targeted disruption of the PRC1.1 complex enhances bone remodeling and promotes bone formation in models of bone loss. The paper addresses the role of epigenetic regulation in bone health, which is crucial for understanding and potentially mitigating age-related skeletal deterioration.

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