Skeletal Anabolism by Simultaneously Targeting the PTH1R and CaSR

同时靶向 PTH1R 和 CaSR 的骨骼合成代谢

• 批准号: 8951598
• 负责人: Christian Yuzon Santa Maria
• 金额: $ 4.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8951598
• 关键词: Address; Adult; Adverse effects; Affect; Aging; Agonist; Alveolar Bone Loss; Anabolism; Animal Model; Biochemical; Bone Injury; Bone Resorption; Bone Tissue; Bone necrosis; Calcium; Calcium-Sensing Receptors; Cell Survival; Cells; Chronic; Combined Modality Therapy; Dental; Dentures; Deterioration; Development; Dihydroxycholecalciferols; Disease; Dose; Economics; Epidemic; Estrogens; FDA approved; Failure; Fellowship; Fostering; Foundations; Fracture; Goals; Growth; Healed; Health; Homeostasis; Hypercalcemia; Hyperparathyroidism; Implant; In Vitro; Injection of therapeutic agent; Intestines; Jaw; Kidney; Knock-out; Knockout Mice; Lead; Mandible; Mandibular Fractures; Methods; Molecular; Morbidity - disease rate; Mus; Oncogenic; Oral; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporotic; PTH gene; Patients; Predisposition; Receptor Gene; Regimen; Risk; Safety; Scientist; Serum; Site; Skeleton; Stem cells; Structure; Testing; Tibial Fractures; Time; Tooth Loss; Training; Treatment Protocols; Vertebral Bone; Woman; Work; bone; bone loss; bone mass; bone strength; bone turnover; career; craniofacial; extracellular; falls; healing; hormone therapy; improved outcome; injury and repair; loss of function; men; mouse model; novel; osteoblast differentiation; osteoporotic bone; osteoprogenitor cell; osteosarcoma; parathyroid hormone (1-34); pre-clinical; prevent; public health relevance; receptor expression; repaired; response; skeletal; substantia spongiosa

DESCRIPTION (provided by applicant): Osteoporosis is a disease characterized by accelerated bone loss and deterioration of structural integrity of bone tissue, which lead to bone fracture susceptibility. This debilitating disease results when the rate of bone resorption by osteoclasts (OCLs) is greater than the rate of bone formation by osteoblasts (OBs). Current evidence shows that appendicular and vertebral bone as well as the craniofacial and oral bone structures are affected, resulting in reduced jawbone mass and periodontal bone loss, which complicates dental treatments. Intermittent parathyroid hormone (PTH) administration is the only FDA-approved therapy that produces bone anabolism and enhances bone injury repair. However, PTH dosing is limited to a short-term use with a relatively low dose due to its adverse hypercalcemic effects and oncogenic potential in bone. Therefore, a better understanding of the molecular and cellular mechanisms underlying the osteoanabolic actions and adverse effects of PTH is required to devise strategies to enhance PTH therapy. We hypothesize that the activation of the extracellular calcium-sensing receptors (CaSR) in the OB lineages are essential steps in producing osteoanabolic responses to intermittent PTH at appendicular and craniofacial sites and that combined treatment with a calcimimetic will enhance the osteoanabolic effects of intermittent PTH by simultaneously potentiating CaSR activities in OBs in normal and fracture bones. To test this hypothesis, a pharmacological approach will be taken to determine whether activating CaSRs in OBs by co-injecting the calcimimetic NPS-R568 enhances osteoanabolism of PTH in mouse models of aging and estrogen deficiency without producing hypercalcemia. This application aims to establish whether calcimimetics enhance anabolism of intermittent PTH by extending its anabolic window and/or by increasing its capacity to build bone. This will be achieved by assessing temporal changes in structural bone parameters, bone-forming and bone-resorbing rates histomorphometrically, numbers of stem cells in bone, and serum bone turnover markers. A loss-of- function approach using an OB-specific CaSR-KO mouse model with the combined regimens followed by biochemical and skeletal analysis will be taken to ascertain whether CaSR expression is required for (i) the growth, survival, and maturation of early OBs, and (ii) the mineralizing functions of mature OBs in the response of the cells to PTH and combined PTH/calcimimetic treatments. Using similar methods, it will be determined whether co-administration of NPS-R568 and PTH produces more robust healing of tibial and mandibular fractures than administration of PTH alone in adult mice. This work will reveal novel synergistic actions of intermittent PTH and Ca2+ in producing skeletal anabolism and establish preclinical regimens to restore osteoporotic skeleton and accelerate bone fracture repair.

描述（由申请人提供）：骨质疏松症是一种以骨质加速流失和骨组织结构完整性恶化为特征，导致骨折易感性的疾病。当破骨细胞（OCLs）的骨吸收速率大于成骨细胞（OBs）的骨形成速率时，这种使人衰弱的疾病就会发生。目前的证据表明，阑尾骨和椎骨以及颅面和口腔骨结构受到影响，导致颌骨质量减少和牙周骨丢失，这使牙科治疗复杂化。间歇性甲状旁腺激素（PTH）管理是唯一fda批准的治疗产生骨合成代谢和增强骨损伤修复。然而，甲状旁腺激素的剂量仅限于短期使用，剂量相对较低，因为它具有不利的高钙效应和骨致癌潜力。因此，需要更好地了解甲状旁腺激素骨合成代谢作用和不良反应的分子和细胞机制，以制定加强甲状旁腺激素治疗的策略。我们假设OB谱系中细胞外钙敏感受体（CaSR）的激活是产生间歇性甲状旁腺激素（PTH）在附属骨和颅面部位的骨合成代谢反应的必要步骤，并且通过同时增强正常骨和骨折骨OB中CaSR的活性，结合钙化剂治疗将增强间歇性甲状旁腺激素的骨合成代谢作用。为了验证这一假设，将采用药理学方法来确定通过联合注射拟钙化物NPS-R568激活OBs中的CaSRs是否能在衰老和雌激素缺乏的小鼠模型中增强PTH的骨合成代谢而不产生高钙血症。本应用旨在确定是否石灰化剂通过延长其合成代谢窗口和/或通过增加其构建骨骼的能力来增强间歇性甲状腺激素的合成代谢。这将通过评估骨结构参数、骨形成和骨吸收率、组织形态计量学、骨干细胞数量和血清骨转换标志物的时间变化来实现。使用ob特异性CaSR- ko小鼠模型，结合生化和骨骼分析，将采用功能缺失方法来确定CaSR表达是否需要(i)早期ob的生长、存活和成熟，以及（ii）成熟ob在细胞对甲状旁腺激素和甲状旁腺激素/拟钙化联合治疗的反应中的矿化功能。使用类似的方法，将确定在成年小鼠中，NPS-R568和PTH联合使用是否比单独使用PTH更能促进胫骨和下颌骨折的愈合。这项工作将揭示间歇性甲状旁腺激素和Ca2+在产生骨骼合成代谢中的新的协同作用，并建立临床前方案，以恢复骨质疏松的骨骼和加速骨折修复。