Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Bone biology Article has an altmetric score of 2

The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling

  • Text
  • PDF
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

×

Figure 1

P2ry12–/– mice were protected from age-associated bone loss.

Options: View larger image (or click on image) Download as PowerPoint

P2ry12–/– mice were protected from age-associated bone loss.
 
(A–C) Th...
(A–C) The primary and secondary spongiosa of the tibias of age- and sex-matched WT and P2ry12–/– littermate mice were analyzed by μCT scanning. (A) Representative 3D reconstructions of trabecular bone. Scale bar: 200 μm. (B) Calculation of BV/TV and (C) BMD. Tb, trabecular bone. (D and E) Serum concentration of CTX and P1NP measured by ELISA. (F) Bone formation was visualized by calcein (first) and alizarin red (second) double-labeling and visualized in the trabecular bone. Scale bars: 200 μm. MAR and BFR are shown (G and H). Bone histology, representative TRAP staining (I). Scale bar: 300 μm. (J–M) Quantification of OB and OC cells in the primary and secondary spongiosa of the femur. OC number and OC surface per bone surface, OB number and OB surface per bone surface are shown. Data represent mean ± SD. n = 6. *P < 0.05; **P < 0.01; ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 2 X users
Highlighted by 1 platforms
78 readers on Mendeley
See more details