VSIG4 inhibits RANKL-induced osteoclastogenesis by suppressing Nrf2-mediated reactive oxygen species production
Osteoporosis is a common systemic skeletal disorder especially in postmenopausal women due to excessive production and activation of osteoclasts. However, current anti-osteoporotic drugs used in clinical practice may cause some side effects. Thus, it is necessary to further explore the potential mechanisms regulating the differentiation of osteoclast and develop novel targets for the treatment of osteoporosis. In our study, we found that VSIG4 exhibited the most significant decline among VSIG family members. Overexpression of VSIG4 significantly inhibited RANKL-induced osteoclastogenesis and bone resorption function. Mechanismly, the western blot and immunofluorescence results also showed that overexpression of VSIG4 attenuated the expression of osteoclast marker genes and the activation of MAPK and NF-?B signaling pathways. We found that overexpression of VSIG4 could suppress the generation of reactive oxygen species (ROS) and activate the expression of Nrf2 and its downstream antioxidant enzymes. ML385, a potent Nrf2 inhibitor, was found to reverse the inhibitory impact of VSIG4 on osteoclast differentiation. Consistently, overexpression of VSIG4 also rescued OVX-induced bone loss and attenuated the activation of osteoclasts in vivo. Taken together, our results indicated that VSIG4 could be an novel target to address postmenopausal osteoporosis by suppressing osteoclast formation via regulation of Nrf 2-mediated ROS generation. Overall design: To investigate the expression changes of VSIG4 during RANKL-induced osteoclastogenesis, bone marrow monocytes(BMMs) were treated with RANKL(50ng/ml) for 0 or 5 days. we then performed gene expression profiling analysis using data obtained from RNA-seq of BMMs at two time points.