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<p>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 <i>Kdm2b</i> 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.</p>

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Targeted disruption of PRC1.1 complex enhances bone remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月8日

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  • 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

摘要

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.