Pla2g7 regulates bone homeostasis via Alox12/12-HETE/Gpr31 signaling axis.

Bone homeostasis mainly depends on the equilibrium of osteoclasts and osteoblasts, overactivated osteoclasts play a pivotal role in the progression of osteoporosis. Here, we revealed that Pla2g7 (phospholipase A2 group VII) was positively correlated with bone resorption in clinic. By single-cell RNA-seq data analysis, Pla2g7 was found highly enriched in osteoclasts along the developmental trajectory, which promoted osteoclast differentiation. Inhibition of Pla2g7 by Darapladib impaired both human and mice osteoclast differentiation, meanwhile, Pla2g7-deficient mice showed higher bone mass and restored the ovariectomy-induced bone loss. Mechanistically, we identified that Alox12 (arachidonate 12-lipoxygenase) mediated-arachidonic acid metabolism is a key determinant in Pla2g7 enhanced osteoclast differentiation. Its metabolite 12-HETE (12-hydroxyeicosatetraenoic acid) activated Gpr31 to regulate osteoclast formation via p38 MAPK pathway and mitochondrial energy metabolism. Collectively, our study uncovers an Alox12/12-HETE/Gpr31 axis that regulates Pla2g7-induced osteoclast differentiation, and provides a new insight for osteoporosis treatment.