Histone Demethylase KDM5C Deficiency Inhibits Bone Formation and Fracture Healing in Aged Mice by Epigenetically Activating Erdr1

Background: Fractures are one of the most common clinical injuries, especially for elders with osteoporosis. KDM5C specifically demethylate di- and tri-methylated lysine 4 on histone. It is frequently mutated in X-linked intellectual disability patients exhibiting physical and behavioral abnormalities. However, it is unclear whether KDM5C plays a role in bone formation and fracture repair.Methods: We used KDM5C conventional knockout mice model to investigate its role on bone formation. Western blotting, immunofluorescence staining, RNAseq, and ChIP assay were applied to demonstrate the molecular mechanism. Open femur fracture model was used to investigate the effects of KDM5C and Erdr1 on fracture healing.Findings: We found that the expression level of KDM5C was constantly increased during the osteogenesis of MSCs. Silencing endogenous KDM5C inhibited osteogenic differentiation of MSCs in vitro and KDM5C knockout mice displayed decreased bone mass and abnormal bone development. Further, RNA-seq analysis showed that PI3K-Akt signaling pathway and Erdr1 were most significantly influenced by KDM5C. KDM5C deficiency resulted in increased Erdr1 expression by histone modification. While knockdown of Erdr1 could promote osteogenesis and angiogenesis. Finally, using an experimental mouse femur fracture model, we found that KDM5C deficiency would impair fracture healing, which could be rescued by silencing Erdr1. More importantly, we found that KDM5C was decreased in bone samples of osteoporotic fracture.Interpretation: Taken together, these results showed that KDM5C was a novel regulator of osteogenesis and angiogenesis. KDM5C or Erdr1 might be potential therapeutic targets for the treatment of fracture and other bone diseases.Funding: The work was supported by grants from the National Natural Science Foundation of China (NSFC No. 81871778).Declaration of Interest: The authors declare that they have no conflict of interest.Ethical Approval: All surgical interventions, treatments and postoperative animal care procedures were strictly performed in accordance with the guidelines for Animal Welfare and Ethics Committee of Guangzhou University of Chinese medicine. Human bone tissues were obtained in the Second Affiliated Hospital of Guangzhou Medical University. All animal experiments were performed in accordance with protocols that were approved and authorized by the Animal Welfare and Ethics Committee of Guangzhou University of Chinese medicine.