Biasing OGR1 signaling to optimizing PTH therapeutic effect

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Project Summary/Abstract Osteoporosis is a common metabolic bone disease and results from a disruption of the balance between osteoblastic bone formation and osteoclastic bone resorption. Intermittent administration of PTH increases bone mass, whereas continuous infusion of PTH promotes bone resorption. However, the mechanisms underlying the distinct signaling pathways that generate this skeletal response remain poorly understood. It is well accepted that acidosis suppresses osteoblastic bone formation and augments osteoclastic bone resorption. Ovarian cancer G protein-coupled receptor 1 (OGR1), a member of the proton sensing GPCR family, transduces extracellular pH signals primarily into Gq/PLC signaling in bone. Both published studies and our preliminary data have demonstrated PTH receptor and OGR1 promote a concomitant activation of anabolic Gαs/cAMP and catabolic Gαq/PLC signaling pathways. It has been observed that some benzodiazepines such as lorazepam cause bone fractures. We have demonstrated that lorazepam acts as a Gq-biased allosteric modulator of OGR1 to preferentially induce Gq/PLC signaling. These findings suggest that the association between lorazepam use and bone fracture may be ascribed to OGR1 biased signaling. Our preliminary data show that continuous PTH treatment promotes lactic acid production and increases OGR1 expression, and that sulazepam (another benzodiazepine) acts as an allosteric modulator of OGR1 to bias OGR1 signaling toward the Gαs/cAMP (therapeutic) pathway. Based on these findings, we hypothesize that OGR1 mediates the catabolic effect of continuous PTH on bone, and sulazepam can bias OGR1 signaling to “tune” PTH receptor signaling toward its therapeutic pathway. Two specific aims are proposed to test this hypothesis. Aim 1 will establish whether sulazepam converts continuous PTH catabolic effect to bone anabolism in vivo. In Aim 2, we will characterize the mechanisms by which sulazepam reverses the catabolic effect of PTH by promoting biased OGR1 signaling in vitro. We predict that sulazepam but not lorazepam shifts the catabolism of continuous PTH toward an anabolic effect on bone by promoting Gs-biased OGR1 signaling. Successful completion of the proposed studies will not only advance our understanding complex effects of PTH on bone, but also provide evidence that targeting Gs- biased OGR1 signaling can shift continuous PTH treatment toward to therapeutic effect.