BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Combined long-acting PTH and calcimimetics actions on skeletal anabolism

BCCMA：针对和抵抗不利于骨骼的条件的基础研究（遏制骨折）：长效 PTH 和拟钙剂联合作用对骨骼合成代谢的作用

• 批准号: 10531570
• 负责人: Wenhan Chang
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10531570
• 关键词: Ablation; Acceleration; Address; Adverse effects; Affect; Aging; Anabolism; Award; Bone Diseases; Bone Regeneration; Bone Resorption; Bone callus; Calcium-Sensing Receptors; Cartilage; Cells; Clinical; Clinical Management; Clinical Trials; Clinical Trials Design; Collaborations; Combined Modality Therapy; Cyclic AMP; Development; Diagnosis; Disease; Disease model; Dose; Early Diagnosis; Economic Burden; Endosomes; Ensure; Estrogen deficiency; Etiology; Family; Fracture; Funding; Genes; Goals; Growth; Health; Healthcare Systems; Homeostasis; Hospitals; Hybrids; Hypercalcemia; Imaging technology; Individual; Injectable; Injections; Investigation; Mediating; Minerals; Molecular; Morbidity - disease rate; Mus; Musculoskeletal Pain; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporosis prevention; Osteoporotic; Outcome Measure; PTH gene; Patients; Peptides; Pharmaceutical Preparations; Pilot Projects; Population; Pre-Clinical Model; Prevention approach; Proliferating; Quality of life; Receptor Activation; Regimen; Rehabilitation therapy; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Skeleton; Technical Expertise; Testing; Therapeutic; Time; Veterans; analog; bone; bone fracture repair; bone health; bone loss; bone mass; bone repair; clinically relevant; common treatment; cortical bone; cost; design; effective therapy; extracellular; first-in-human; fracture risk; fragility fracture; healing; high risk; hormonal signals; hormone analog; hormone therapy; improved; in vitro Model; in vivo; innovation; insight; knock-down; knockout gene; live cell imaging; male; mineralization; mortality; novel; novel strategies; osteoporotic bone; overexpression; parathyroid hormone-related protein; positive allosteric modulator; prevent; receptor; research study; side effect; skeletal; socioeconomics; substantia spongiosa; therapy adherence; tool; treatment effect; treatment strategy; young adult

To ensure aging Veterans remain active and mobile with as little musculoskeletal pain as possible, new approaches to the prevention of osteoporosis and promotion of timely bone regeneration following a fracture are necessary. This collaborative research study brings together a group of VA investigators with diverse perspectives and insights of disease models and complementary technical expertise, to synergistically attack a major clinical problem. i.e., a bone fracture, that leads to high morbidity and mortality among Veterans. The overall research strategy of each integrated project is to use pre-clinical models of diseases that either weaken bone or delay bone repair, to investigate novel ways to enhance the ability of parathyroid hormone (PTH) to promote bone formation, and to assess disease and treatment effects on bone in a unified, stringent manner. Already under-diagnosed and under-treated, osteoporosis is likely to increase the number of fragility fractures being treated at VA hospitals without novel tools for early detection and novel treatment strategies that circumvent the rare but devastating side effects of current therapies that inhibit bone loss. Addressing this unmet clinical need, the overall aims are to identify therapeutic strategies to improve bone health among Veterans and to enhance the bone anabolism of PTH signaling. The collaboration will address the overarching hypothesis: health problems disproportionately affecting Veterans activate signaling pathways that increase bone resorption, suppress bone formation, or impede the transition of cartilage to bone in a fracture callus such that improvements in the clinical management of osteoporosis lie in understanding how these health problems hurt bone health. This specific proposal is based on a large body of investigations that demonstrate a central role of the Ca2+- sensing receptor (CaSR) in mediating systemic mineral homeostasis by counteracting the calciotropic activities of PTH and in synergizing the anabolic effects of PTH on bone as well as the recent studies that show robust anabolic actions of a long-acting PTH1-34/PTHrP hybrid analog, namely, LAPTH. We will test the hypothesis that co-injections of calcimimetics with LAPTH produce much more robust osteoanabolism than the current PTH1-34 therapy without producing hypercalcemia to accelerate rehabilitation of aging- or estrogen deficiency- induced osteoporotic skeletons by activating CaSRs in mature OBs, OCYs, and OCLs through 3 highly integrated specific Aims. Aim 1 will first establish the clinical relevance of the combined LAPTH/calcimimetic regimen by (a) optimizing the drug doses needed to produce maximal skeletal anabolism without producing hypercalcemia and the related complications in aging male mice and ovariectomized mice; and (b) determining whether an antiresorptive treatment is required to retain the newly formed bone and ultimately resist bone fracture following the combined treatment. Aim 2 will (a) define the role of CaSR in mature OB/osteocytes in mediating the anabolic actions of the combined LAPTH/NPS-R568 treatment by assessing changes in mineral and skeletal parameters and perilacunar remodeling (PLR) activities in mice with their Casr genes ablated in those cells; (b) delineate the underlying cell-autonomous mechanisms by comparing the effects of the compounds individually and in combination on the proliferation, survival, differentiation, and mineralizing functions of primary OBs and osteocytic MLO-Y4 cells with or without CaSR overexpression or knockdown in culture; and (c) elucidate signaling cross-talk between CaSR and PTH1R in mature OBs and MLO-Y4 cells by single live cell imaging technology. Aim 3 will (a) define the role of OCL CaSR in preventing the development of hypercalcemia and in mediating osteoanabolic effects of the combined LAPTH/NPS-R568 treatment by assessing changes in mineral and skeletal homeostasis in mice with their Casr genes knocked-out in OCLs; and (b) define the underlying mechanisms by examining the effects of the compounds on the growth, survival, differentiation, and bone- resorbing functions of cultured OCLs overexpressing or lacking CaSR. Successful completion of the study will provide essential information for designs of “first-in-man” trials for more effective treatments of osteoporosis.

为了确保老年退伍军人保持活跃和活动能力，并尽可能减少肌肉骨骼疼痛，新的 预防骨质疏松症和促进骨折后及时骨再生的方法有 这项合作研究汇集了一组不同背景的 VA 研究人员。 疾病模型的观点和见解以及互补的技术专业知识，以协同攻击 主要的临床问题，即骨折，导致退伍军人的高发病率和死亡率。 每个综合项目的总体研究策略是使用疾病的临床前模型，这些模型要么削弱 骨或延迟骨修复，研究增强甲状旁腺激素（PTH）能力的新方法 促进骨形成，并以统一、严格的方式评估疾病和治疗对骨的影响。 由于骨质疏松症的诊断和治疗不足，骨质疏松症可能会增加脆性骨折的数量 在退伍军人管理局医院接受治疗，没有新的早期检测工具和新的治疗策略， 避免目前抑制骨质流失的疗法罕见但具有破坏性的副作用，解决这一未得到满足的问题。 临床需求，总体目标是确定改善退伍军人和老年人骨骼健康的治疗策略 增强 PTH 信号的骨合成代谢 该合作将解决以下总体假设： 健康问题对退伍军人的影响不成比例，会激活信号通路，增加骨吸收， 抑制骨形成，或阻碍骨折愈伤组织中软骨向骨的转变，从而改善 骨质疏松症的临床治疗关键在于了解这些健康问题如何损害骨骼健康。 这一具体建议基于大量研究，这些研究证明了 Ca2+- 的核心作用 传感受体（CaSR）通过抵消促钙活性来介导全身矿物质稳态 PTH 和协同 PTH 对骨的合成代谢作用以及最近的研究表明， 长效 PTH1-34/PTHrP 混合类似物（即 LAPTH）的合成代谢作用我们将检验该假设。 拟钙剂与 LAPTH 的联合注射比目前的药物产生更强劲的骨合成代谢 PTH1-34 治疗不会产生高钙血症，可加速衰老或雌激素缺乏的康复 通过 3 个高度整合的激活成熟 OB、OCY 和 OCL 中的 CaSR 来诱导骨质疏松骨骼 具体目标 1 将首先通过以下方式确定 LAPTH/拟钙剂组合方案的临床相关性。 (a) 优化产生最大骨骼合成代谢而不产生高钙血症所需的药物剂量 以及衰老雄性小鼠和卵巢切除小鼠的相关并发症；以及（b）确定是否存在 需要进行抗吸收治疗以保留新形成的骨骼并最终抵抗骨折后的骨折 联合治疗的目标 2 将 (a) 定义成熟 OB/骨细胞中 CaSR 在介导合成代谢中的作用。 通过评估矿物质和骨骼参数的变化来评估 LAPTH/NPS-R568 联合治疗的作用 以及 Casr 基因在这些细胞中被消除的小鼠的腔周重塑 (PLR) 活动；(b) 描绘了 通过比较单个化合物的作用和在中的作用来了解潜在的细胞自主机制 组合对原代 OB 的增殖、存活、分化和矿化功能的影响 培养中具有或不具有 CaSR 过度表达或敲低的骨细胞 MLO-Y4 细胞；以及 (c) 阐明 通过单活细胞成像观察成熟 OB 和 MLO-Y4 细胞中 CaSR 和 PTH1R 之间的信号串扰 目标 3 将 (a) 定义 OCL CaSR 在预防高钙血症发生和预防中的作用。 通过评估矿物质的变化来调节 LAPTH/NPS-R568 联合治疗的骨合成代谢作用 OCL 中 Casr 基因被敲除的小鼠的骨骼稳态；以及 (b) 定义了潜在的机制； 通过检查化合物对生长、存活、分化和骨的影响来研究机制 培养的 OCL 过度表达或缺乏 CaSR 的重吸收功能将成功完成该研究。 为设计“首次人体”试验提供重要信息，以更有效地治疗骨质疏松症。