The effect of ROS-YAP crosstalk on osteoimmune response orchestrating osteogenesis

ABSTRACTBone defect repair is a common medical concern. In spite of various existing treatments, its management still requires improvement. Here we show that YAP, a downstream signaling of Hippo pathway, might interplay with redox oxygen species (ROS) and modulate osteoimmunology, which refers to the interaction between immune and skeletal system during bone defect repair. We modulated the ROS level of RAW264.7 cells and found YAP level was reversely regulated. Meanwhile, we detected the feedback of YAP on oxidation level. The results demonstrated that the antioxidant enzyme expression was in proportion to the YAP level of RAW264.7 cells. Additionally, indirect coculture system was applied and it indicated that RAW264.7 cells under oxidative stress could impede proliferation and migration ability of MC3T3-E1 pre-osteoblasts. Consistently, in vivo experiment verified high oxidant level slowed down mice osteogenesis during bone defect repair, while antioxidant and upregulation of YAP accelerated this process. Additionally, we established a mouse model with YAP conditional knockout in macrophages. The results identified that deficiency of YAP in macrophages negatively affected bone defect repair in vivo. In summary, our study indicated that ROS and YAP could jointly modulate osteogenesis via their effect on osteoimmunology.ABBREVIATIONS:GPX4, glutathione peroxidase 4; NAC, N-Acetyl-L-cysteine; qRT-PCR, real-time quantitative PCR; ROS, reactive oxygen species; Tb.N, trabecular number; Tb.Sp, trabecular separation.