Lysophosphatidic acid stimulates osteoclast fusion through OC-STAMP and P2X7 receptor signaling

Bone is continuously remodeled by bone formation and resorption, and cooperative bone metabolism is precisely regulated to maintain homeostasis. Osteoclasts, which are responsible for bone resorption, are differentiated through multiple steps that include cell fusion at the last step of differentiation, yielding multinuclear cells. However, the factors involved in and the precise mechanism of cell fusion are still unknown. To determine the molecules involved in osteoclast fusion, we examined the effect of lysophosphatidic acid (LPA), which has been reported to participate in the progression of cancer bone metastasis. LPA had no effect on osteoclast formation and bone resorption under receptor activator of nuclear factor kappa B ligand (RANKL) conditions, whereas LPA stimulated osteoclast fusion, thereby causing increased osteoclast diameter and bone resorptive capacity under a RANKL-limited condition. This result encouraged us to assess what molecules are needed for LPA-stimulated osteoclast fusion. Interestingly, LPA stimulated osteoclast stimulatory transmembrane protein (OC-STAMP) and P2X7 receptor mRNA expression during osteoclast fusion under a RANKL limiting condition. siRNA-induced OC-STAMP or P2X7 receptor knockdown significantly suppressed the LPA-stimulated increase in osteoclast diameter and bone resorptive capacity in differentiating cultures. Using cyclosporin A as an inhibitor, we revealed that NF-ATc1 directly regulates OC-STAMP and P2X7 receptor expression during LPA-stimulated osteoclast fusion. These results suggest that LPA is a critical regulator of osteoclast fusion by inducing the OC-STAMP and P2X7 receptor. Therefore, LPA signaling might be useful to help understand their effects on osteoclast formation and as a therapeutic target for patients with pathologically increased osteoclast formation.ope