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ABSTRACT As the aging population continues to grow, the incidence of osteoporotic fractures increases and is compounded by our lack of therapeutic strategies that increase bone formation. Although exercise and physical activity play a key role in maintaining bone mass throughout our lives, the loads and exertion required to elicit an anabolic response becomes exceedingly difficult to achieve with age. Based on previous work, the P2Y2 receptor offers a unique therapeutic target to increasing bone mass by modifying the mechanotransduction. Others have also shown P2Y2 to have a negative effect on osteoblast function. However, the extent to which inhibiting P2Y2 pharmaceutically improves bone mass or the mechanotransduction of bone remains unknown. Our central hypothesis for this study states that inhibiting P2Y2 activity can enhance the anabolic response to loading in an aging population. To test this hypothesis, the anabolic response to exercise was examined by treating adult mice, which typically display a minimal response, with the P2Y2 inhibitor AR‐C118925XX (ARC). Our findings from this study demonstrate that ARC treatment of adult mice increases periosteal bone formation in response to exercise. The enhanced response to exercise was characterized by a reduction in osteocytes' induction of osteoclast activity. Endocortical bone formation also increased with treatment independently of exercise, providing gains in mechanical strength and tissue level properties. Overall, inhibiting P2Y2 activation has a beneficial effect on bone formation and the anabolic response to loading, namely by limiting osteoclast activation. [ABSTRACT FROM AUTHOR]

Osteocytes' response to dynamic loading plays a crucial role in regulating the bone mass but quickly becomes saturated such that downstream induction of bone formation plateaus. The underlying mechanisms that downregulate osteocytes' sensitivity and overall response to loading remain unknown. In other cell types, purinergic signaling through the P2Y2 receptor has the potential to downregulate the sensitivity to loading by modifying cell stiffness through actin polymerization and cytoskeleton organization. Herein, we examined the role of P2Y2 activation in regulating osteocytes' mechanotransduction using a P2Y2 knockout cell line alongside conditional knockout mice. Our findings demonstrate that the absence of P2Y2 expression in MLO-Y4 cells prevents actin polymerization while increasing the sensitivity to fluid flow-induced shear stress. Deleting osteocytes' P2Y2 expression in conditional-knockout mice enabled bone formation to increase when increasing the duration of exercise. Overall, P2Y2 activation under loading produces a negative feedback loop, limiting osteocytes' response to continuous loading by shifting the sensitivity to mechanical strain through actin stress fiber formation. [ABSTRACT FROM AUTHOR]