Biasing OGR1 signaling to optimizing PTH therapeutic effect

偏向 OGR1 信号传导以优化 PTH 治疗效果

• 批准号: 9896526
• 负责人: Bin Wang
• 金额: $ 20.59万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9896526
• 关键词: Acidosis; Anabolic Agents; Anabolism; Anxiety; Apoptosis; Benzodiazepines; Binding; Bone Marrow Cells; Bone Resorption; Catabolism; Coculture Techniques; Complex; Continuous Infusion; Coupling; Cyclic AMP; Data; Dinoprostone; Equilibrium; Family; Fracture; G-Protein-Coupled Receptors; GPR68 gene; GTP Binding; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Gene Expression; Goals; Immunoprecipitation; Implant; In Vitro; Infusion procedures; Knockout Mice; Lactic acid; Lorazepam; Mediating; Metabolic Bone Diseases; Modeling; Molecular; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; PTGS2 gene; PTH gene; Parathyroid Hormone Receptor; Pathway interactions; Production; Protons; Publishing; Pump; Receptor Signaling; Scanning; Signal Pathway; Signal Transduction; Sleeplessness; Specificity; TNFSF11 gene; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Treatment Efficacy; Wild Type Mouse; base; bone; bone loss; bone mass; cost effective; design; extracellular; in vivo; insight; member; microCT; mineralization; osteoblast differentiation; prevent; response; skeletal

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.

项目概要/摘要 骨质疏松症是一种常见的代谢性骨病，是由于骨与骨之间的平衡被破坏造成的。 成骨细胞骨形成和破骨细胞骨吸收。间歇性施用 PTH 可增加骨质 质量，而持续输注 PTH 可促进骨吸收。然而，其背后的机制 产生这种骨骼反应的不同信号传导途径仍然知之甚少。它被广泛接受 酸中毒抑制成骨细胞骨形成并增强破骨细胞骨吸收。卵巢 癌症 G 蛋白偶联受体 1 (OGR1) 是质子感应 GPCR 家族的成员，可转导 细胞外 pH 信号主要转化为骨中的 Gq/PLC 信号。已发表的研究和我们的初步数据 已证明 PTH 受体和 OGR1 促进合成代谢 Gαs/cAMP 的同时激活， 分解代谢 Gαq/PLC 信号通路。据观察，一些苯二氮卓类药物如劳拉西泮 导致骨折。我们已经证明劳拉西泮可以作为 OGR1 的 Gq 偏向变构调节剂 优先诱导 Gq/PLC 信号传导。这些发现表明劳拉西泮的使用与 骨折可能归因于 OGR1 信号偏向。我们的初步数据表明，连续 PTH 治疗可促进乳酸产生并增加 OGR1 表达，并且舒拉西泮（另一种 苯二氮卓）作为 OGR1 的变构调节剂，使 OGR1 信号偏向 Gαs/cAMP （治疗）途径。基于这些发现，我们假设 OGR1 介导分解代谢作用 骨骼上的连续 PTH，而舒拉西泮可以偏向 OGR1 信号传导，从而“调整”PTH 受体信号传导至其方向 治疗途径。提出了两个具体目标来检验这一假设。目标 1 将确定是否 舒拉西泮将持续的 PTH 分解代谢作用转化为体内骨合成代谢。在目标 2 中，我们将描述 舒拉西泮通过促进偏向 OGR1 信号传导逆转 PTH 分解代谢作用的机制 体外。我们预测，舒拉西泮（而不是劳拉西泮）会将持续性 PTH 的分解代谢转变为合成代谢。 通过促进 Gs 偏向的 OGR1 信号传导对骨骼产生影响。成功完成拟议的研究不会 不仅促进了我们对 PTH 对骨骼的复杂影响的理解，而且还提供了针对 Gs- 的证据 偏向的 OGR1 信号传导可以使持续 PTH 治疗转向治疗效果。