LAUSR

&NA; Recently, several plexins and semaphorins have been associated with osteoclastogenesis, a vital process for bone remodeling. Plexin‐A2 is implicated in bone homeostasis, however, whether it plays a role in osteoclastogenesis and the underlying mechanism remain unknown. We show that plexin‐A2 expression is upregulated during RANKL‐induced osteoclastogenesis. In addition, the soluble Sema6A fused with IgG1 Fc region (Fc‐Sema6A) interacts with plexin‐A2 from cell lysates of osteoclasts, suggesting that plexin‐A2 acts as a receptor of Sema6A in osteoclasts. Moreover, Sema6A treatment stimulates RANKL‐induced osteoclastogenesis, and this effect is abolished when plexin‐A2 is neutralized, which illustrates an indispensable role of plexin‐A2 in mediating Sema6A effect on osteoclastogenesis. Mechanistically, Sema6A‐plexin‐A2 axis enhances RANKL‐induced activation of PLC&ggr; as well as downstream target NFATc1, one master transcriptional factor of osteoclastogenesis. Lastly, inhibition of PLC&ggr; by pharmacological inhibitor U73122 abrogates Sema6A‐stimulated NFATc1 activation and RANKL‐induced osteoclastogenesis, thus demonstrating that the PLC&ggr;‐mediated NFATc1 activation accounts for the promotive role of Sema6A‐plexin‐A2 axis in RANKL‐induced osteoclastogenesis. Taken together, this study uncovers a novel role of Sema6A and plexin‐A2 in osteoclastogenesis, and also offers them as possible therapeutic targets in the intervention of osteolytic diseases.