Gpr54 Suppresses Osteoclast Formation And Function

Gpr54 is a member of rhodopsin family G protein-coupled receptor, and its endogenous ligand is Kisspeptin encoded by kiss1. The kiss1/Gpr54 signaling pathway is crucial for the initiation and development of puberty via regulation of hypothalam-pituitary-gonadal axis. Considering bone development is impotant characteristic of adolescent development, and many puberty-related hormones have been reported to participate in regulation of osteoclast differentiation and activation directly, we hypothesize that Gpr54 directly regulates osteoclast development and bone resorption.In this study, we analyze the bone phenotype of Gpr54-/- mice and found Gpr54-/-mice exhibit severe osteoporosis due to osteoclast over-activation. To exclude the possibility that bone loss in Gpr54-/- mice is the result of hypogonadal caused by Gpr54 deficiency, we performed both castration and ovariectomy in mice before adolescence. The results show that osteoclasts are also over-activated in Gpr54-/- mice. In the vitro, differentiation assay Gpr54-/- bone marrow monocytes displays enhanced osteoclast fusion, and bone resorption compared with that of Gpr54+/+ cell. On the other hand, Kisspeptin-10(Kp-10), the ligand for Gpr54, has an adverse effect on osteoclast activation in vitro. These results indicate that Gpr54 is possibly involved in regulation of cytoskeletal reorganization and osteoclast motility. In the molecular mechanism, our results show that knocking out Gpr54 significantly enhance c-Src phosphorylation, while Kp-10 treatment inhibits its phosphorylation in a dose dependent manner.In summary, our results clemostrate that Gpr54 protects bone by inhibiting OC formation and resorption. And Kp-10 treatement can also inhibit osteoclast activation. We further found Kiss1/Gpr54 may regulates osteoclast by participate in regulation of c-Src signaling pathway. Therefore, Gpr54 could be a novel molecular target for treating osteoclast-related diseases.