The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
Xinming Su, … , Michael Rogers, Katherine N. Weilbaecher
Xinming Su, … , Michael Rogers, Katherine N. Weilbaecher
Published September 17, 2012
Citation Information: J Clin Invest. 2012;122(10):3579-3592. https://doi.org/10.1172/JCI38576.
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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

Xinming Su, Desiree H. Floyd, Alun Hughes, Jingyu Xiang, Jochen G. Schneider, Ozge Uluckan, Emanuela Heller, Hongju Deng, Wei Zou, Clarissa S. Craft, Kaiming Wu, Angela C. Hirbe, Dorota Grabowska, Mark C. Eagleton, Sarah Townsley, Lynne Collins, David Piwnica-Worms, Thomas H. Steinberg, Deborah V. Novack, Pamela B. Conley, Michelle A. Hurchla, Michael Rogers, Katherine N. Weilbaecher

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Figure 5

Genetic inhibition of P2RY12 protected mice from tumor-associated bone loss.

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Genetic inhibition of P2RY12 protected mice from tumor-associated bone l...
(A and B) 1 × 104 B16-FL tumor cells (right leg) or PBS (control, left leg) were injected directly into the tibia (n = 6 per group). (A and B) The tumor burden in hind limbs was measured by BLI. (C and D) BV/TV and BMD in the primary and secondary spongiosa of PBS-injected or tumor-bearing tibia were analyzed by μCT. (E) TRAP-stained tibial sections (×4) of WT (top) and P2ry12–/– mice (bottom) 10 days after tumor injection. T, tumor; M, marrow. TRAP+ staining (dark red areas) indicates OC presence. Scale bar: 300 μm. (F) OC number and surface per bone surface in the primary and secondary spongiosa of the tibia are shown in saline-injected tibia (S) (black bars) and tumor-injected tibia (T) (white bars). Data represent mean ± SD. n = 6. *P < 0.05.