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RECEPTORS AND SIGNAL TRANSDUCTION

ATP downregulates P2X₇ and inhibits osteoclast formation in RAW cells

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Submitted 26 August 2003 ; accepted in final form 26 March 2004

Multinucleated giant cells derive from fusion of precursor cells of the macrophage lineage. It has been proposed that the purinoreceptor P2X₇ is involved in this fusion process. Prolonged exposure of macrophages to ATP, the ligand for P2X₇, induces the formation of plasma membrane pores and eventual cell death. We took advantage of this cytolytic property to select RAW 264.7 (RAW) cells that lacked P2X₇ function by maintaining them in ATP (RAW ATP-R cells). RAW ATP-R cells failed to fuse to form multinucleated osteoclasts in response to receptor activator nuclear factor-B ligand, although they did become positive for the osteoclast marker enzyme tartrate-resistant acid phosphatase, and upregulated expression of other osteoclast marker genes. RAW ATP-R cells and wild-type RAW cells expressed similar amounts of P2X₇ protein, but little P2X₇ was present on the surface of RAW ATP-R cells. After ATP was removed from the medium of RAW ATP-R cells, the cells reexpressed P2X₇ on the cell surface, regained sensitivity to ATP, and formed multinucleated osteoclasts. These results suggest that P2X₇ or another protein that is downregulated in concert with P2X₇ is involved either in the mechanics of cell fusion to form osteoclasts or in a signaling pathway proximal to this event. These results also suggest that P2X₇ may be regulated by ligand-mediated internalization and that extracellular ATP may regulate the formation of osteoclasts and other multinucleated giant cells.

macrophage fusion; P2X receptor; purinergic receptor; receptor activator nuclear factor-B