TY - JOUR
T1 - The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
AU - Su, Xinming
AU - Floyd, Desiree H.
AU - Hughes, Alun
AU - Xiang, Jingyu
AU - Schneider, Jochen G.
AU - Uluckan, Ozge
AU - Heller, Emanuela
AU - Deng, Hongju
AU - Zou, Wei
AU - Craft, Clarissa S.
AU - Wu, Kaiming
AU - Hirbe, Angela C.
AU - Grabowska, Dorota
AU - Eagleton, Mark C.
AU - Townsley, Sarah
AU - Collins, Lynne
AU - Piwnica-Worms, David
AU - Steinberg, Thomas H.
AU - Novack, Deborah V.
AU - Conley, Pamela B.
AU - Hurchla, Michelle A.
AU - Rogers, Michael
AU - Weilbaecher, Katherine N.
PY - 2012/10/1
Y1 - 2012/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867183289&partnerID=8YFLogxK
U2 - 10.1172/JCI38576
DO - 10.1172/JCI38576
M3 - Article
C2 - 22996695
AN - SCOPUS:84867183289
SN - 0021-9738
VL - 122
SP - 3579
EP - 3592
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 10
ER -