title: The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling.
abstract: The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.
authors.affiliation: Department of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Xinming
authors.initials: X
authors.lastname: Su
authors.forename: Desiree H
authors.initials: DH
authors.lastname: Floyd
authors.forename: Alun
authors.initials: A
authors.lastname: Hughes
authors.forename: Jingyu
authors.initials: J
authors.lastname: Xiang
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.forename: Ozge
authors.initials: O
authors.lastname: Uluckan
authors.forename: Emanuela
authors.initials: E
authors.lastname: Heller
authors.forename: Hongju
authors.initials: H
authors.lastname: Deng
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Clarissa S
authors.initials: CS
authors.lastname: Craft
authors.forename: Kaiming
authors.initials: K
authors.lastname: Wu
authors.forename: Angela C
authors.initials: AC
authors.lastname: Hirbe
authors.forename: Dorota
authors.initials: D
authors.lastname: Grabowska
authors.forename: Mark C
authors.initials: MC
authors.lastname: Eagleton
authors.forename: Sarah
authors.initials: S
authors.lastname: Townsley
authors.forename: Lynne
authors.initials: L
authors.lastname: Collins
authors.forename: David
authors.initials: D
authors.lastname: Piwnica-Worms
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Steinberg
authors.forename: Deborah V
authors.initials: DV
authors.lastname: Novack
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Conley
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Hurchla
authors.forename: Michael
authors.initials: M
authors.lastname: Rogers
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Weilbaecher
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology*; D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications; D001859:Bone Neoplasms / Q000150:complications / Q000556:secondary; D016723:Bone Remodeling / Q000187:drug effects / Q000502:physiology*; D001862:Bone Resorption / Q000503:physiopathology; D002277:Carcinoma / Q000150:complications / Q000556:secondary; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D000077144:Clopidogrel; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000502:physiology*; D010024:Osteoporosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D010052:Ovariectomy; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D058925:Receptors, Purinergic P2Y12 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D020827:rap1 GTP-Binding Proteins / Q000187:drug effects
chemical_list: D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D013988:Ticlopidine; D020827:rap1 GTP-Binding Proteins