Hdgfr2 Suppresses Osteogenesis Of BMSCs By Balancing Crotonoylation And Acetylation

Hepatoma-derived growth factor (HDGFR2) is a histone methylation reader and plays a critical "switch" role in gene transcriptional regulation. However, its roles in dictating the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is still obscure. we established the HDGFR2-KO mice and investigated the roles of HDGFR2 in governing the osteogenic differentiation of BMSCs in vitro and in the bone injury repair and the suppressed periodontal bone loss models in vivo. Here we show that HDGFR2 knockout in mice leads to attenuated age-related skeleton bone and inflammation-induced periodontal bone mass loss, as well as enhanced bone defect repair capacity. In vitro, HDGFR2-KO facilitates the colony formation and osteogenic differentiation of BMSCs, and vice versa when HDGFR2 is forcedly overexpressed. Mechanistically, depletion of HDGFR2 disrupts the combination with the active regulator of SIRT1(AROS) in a chromatin remodeling complex, subsequently suppresses the histone deacetylase activity of SIRT1, and rebalances the crotonylation and acetylation ratio at H3K18, thus improves the transcription of osteogenic genes, such as RUNX2 and COL1A1. Our findings decipher the machinery of HDGFR2 mediated histone modification code in osteogenesis and bone repair, and provide theoretical basis for bone tissue regeneration.