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P2RY12 and its role in osteoclast activity and bone remodeling


Clopidogrel, a P2RY12 inhibitor, is used therapeutically to reduce cardiovascular risk; this study focuses on the impact of P2RY12 on osteoclasts and bone remodeling. P2RY12 is a receptor for adenosine diphosphate (ADP), which is known to increase osteoclast activity.

Knockout mice that lacked P2RY12 showed both a marked reduction in osteoclast activity and also reduced bone loss due to age, serum transfer arthritis, bone tumors or the osteoporosis that follows ovariectomy. P2RY12+/+ mice treated with clopidogrel were similarly protected from osteolysis due to disease.

Osteoclasts from P2RY12−/− mice showed reduced ability to resorb bone but had intact differentiation markers. These cells did not respond to extracellular ADP, showing no increase in osteoclastic adhesion or bone resorptive activity. Compared to wild-type mice, P2RY12−/− mice also showed lower levels of RAP1 activation after ADP stimulation.

Editor’s comment: These findings need to be considered in light of the recent study showing that therapeutic doses of clopidogrel are associated with an increase in fracture risk due to osteoporosis. It will also be interesting to examine whether P2RY12 inhibition can protect bone in human pathologic conditions where tissue ADP is increased, such as inflammatory disease and bone metastasis.

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