title: P2X7 receptor drives osteoclast fusion by increasing the extracellular adenosine concentration.
abstract: Defects in bone homeostasis are a major health problem. Osteoclast differentiation and activation have a crucial role in bone remodeling in health and disease. Osteoclasts are bone-resorbing cells derived from mononuclear phagocyte progenitors. The key event in osteoclast formation is fusion of mononucleate precursors to form mature multinucleated osteclasts. Here we provide evidence of an absolute requirement for the P2X7 receptor, ATP release, and adenosine signaling in human osteoclast formation, as shown by the following findings: macrophage-colony stimulating factor/receptor activator for nuclear factor-κB ligand (M-CSF/RANKL)-stimulated fusion of human monocytes is fully prevented by an anti-P2X7 mAb, by specific P2X7 pharmacological antagonists, or by inhibition of CD39/NTPDase; fusion-competent monocytes release ATP via the P2X7 receptor; accelerated degradation of released ATP by addition of either apyrase or hexokinase strongly increases fusion; removal of extracellular adenosine by adenosine deaminase blocks, while addition of exogenous adenosine strongly potentiates, fusion; and pharmacologic stimulation of the adenosine A2A receptor increases, while selective A2A blockade inhibits, fusion. These results show that the purinergic axis plays a crucial and as yet undescribed role in osteoclast formation and reconcile previous evidence advocating a key role for either ATP or adenosine receptors in multinucleated giant cell formation.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pellegatti
authors.forename: Simonetta
authors.initials: S
authors.lastname: Falzoni
authors.forename: Giovanna
authors.initials: G
authors.lastname: Donvito
authors.forename: Irma
authors.initials: I
authors.lastname: Lemaire
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D001081:Apyrase / Q000378:metabolism; D002459:Cell Fusion; D015726:Giant Cells / Q000166:cytology*; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000187:drug effects; D058486:Receptors, Purinergic P2X7 / Q000502:physiology*
chemical_list: D053245:RANK Ligand; D043705:Receptor, Adenosine A2A; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D006593:Hexokinase; D001081:Apyrase; D000241:Adenosine