Fractures have an extraordinarily negative impact on individuals’ quality of life and functional status. Nonunion or disability of fracture is a major health issue with important clinical, social, and economic implications. Mesenchymal stem cells (MSCs) play an indispensable role in the initiation of the fracture repair process including the formation of a callus which is replaced by new bone. The use of MSCs in the treatment of fractures is very attractive as they can reduce the time of healing and occurrence of nonunion. However, the effects of MSCs are often hindered by the harsh ischemic micro-environment at the fracture sites, such as low cell survival rate and differentiation in vivo. Histone modifications are one of the most important epigenetic regulations with the ability to control the fate of stem cells. Lysine demethylase 5C (Kdm5c) is frequently mutated in patients with X-linked intellectual disabilities, many of whom exhibit physical and behavioral abnormalities, including epilepsy, short stature, etc. In our previous study, we investigated the de-differentiated MSCs with enhanced osteogenic differentiation capacity and found that Kdm5c might be involved in regulating the properties of dedifferentiated osteogenic MSCs by PCR array. However, it is still unclear whether Kdm5c plays a role in osteogenesis, bone formation, and fracture repair.