A novel treatment for bone fracture repair

骨折修复的新疗法

• 批准号: 9442568
• 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: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9442568
• 关键词: Acute; Adult; Adverse effects; Aging; Agonist; Anabolism; Applications Grants; Bone Diseases; Bone callus; Bone structure; Calcium-Sensing Receptors; Cartilage; Cell Death; Cells; Chondrocytes; Chondrogenesis; Clinical; Clinical Trials; Clinical Trials Design; Contralateral; Data; Debridement; Development; Disease; Dose; Emotional; Environmental Hazards; Exposure to; FDA approved; Family; Fracture; Fracture Healing; Future; Health system; Hematoma; Histologic; Hormone secretion; Hormones; Hypercalcemia; Hyperparathyroidism; Individual; Inflammatory Response; Injections; Injury; Invaded; Mechanics; Mediating; Military Personnel; Minerals; Molecular; Morbidity - disease rate; Mus; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporotic; PTH gene; Parathyroid gland; Patients; Pharmaceutical Preparations; Pharmacy (field); Population; Pre-Clinical Model; Procedures; Production; Psyche structure; Quality of life; Receptor Signaling; Recovery of Function; Regimen; Rehabilitation therapy; Reporting; Risk; Shapes; Signal Transduction; Site; Skeleton; Speed; Stress; Testing; Tibial Fractures; Time; Trauma; Traumatic injury; Treatment Efficacy; Veterans; angiogenesis; base; bone; bone healing; bone mass; bone strength; clinically relevant; cortical bone; extracellular; healing; hormone therapy; improved; mortality; novel; osteochondral tissue; osteogenic; osteoporotic bone; osteosarcoma; prevent; progenitor; recruit; repaired; response; skeletal; substantia spongiosa; synergism; transdifferentiation

Bone fractures pose a significant problem for veterans who suffered from traumatic injury in the line of military duty or from prevalent osteoporotic diseases as a civilian. Intermittent (or daily) administration of parathyroid hormone (PTH) is the only FDA-approved pharmaceutics that produces osteoanabolism to treat osteoporosis. The osteoanabolic action of PTH is based on the ability of the hormone to alter systemic and local factors that promote osteoblast (OB) activity before its stimulation of osteoclast (OCL) activity catches up, creating an “anabolic window” of positive effects on bone mass and structure to restore mechanical integrity of the bone. Intermittent PTH has also been shown to promote chondrogenesis in calluses at early stages of fracture repair in preclinical models. Several clinical trials also demonstrated osteoanabolism of intermittent PTH at fracture sites. Its dosing is, however, limited to a low level and a short duration due to potential adverse effects -- hypercalcemia and induction of osteosarcoma. Our proposal aims to delineate mechanisms underlying the osteoanabolic actions and the hypercalcemic effects of PTH in order to devise new strategies to enhance PTH therapy. Raising [Ca] activates the extracellular calcium-sensing receptors (CaSRs) in chondrocytes and OBs to promote their survival and differentiation and in OCLs to inhibit their survival and bone-resorbing functions. We postulate that the hypercalcemic effect of intermittent PTH is essential for the production of osteoanabolism. A class of allosteric CaSR agonist (or calcimimetics) has been used clinically to treat hyperparathyroidism and hypercalcemia by potentiating extracellular Ca-induced inhibition of PTH secretion in parathyroid cells (PTCs). In this new grant application, we postulate that this compound, when co-injected with intermittent PTH, will not only subside the hypercalcemic side effects of PTH, but also synergize the effects of PTH and enhance skeletal anabolism by activating the CaSRs in chondrocytes, OBs, and OCLs directly. We hypothesize that a concurrent calcimimetic treatment promotes chondro-to-osteo transition and enhances osteoanabolism of intermittent PTH1-34 by activating the CaSRs in chondrocytes, OBs, and/or OCLs to increase fracture repair capacity and concurrently rehabilitate other weakened skeletons. Aim 1 will determine whether simultaneously activating CaSRs in PTCs, chondrocytes, OBs, and OCLs by systemic co-administration of R568 with PTH1-34 abrogates hypercalcemia and produces more robust osteoanabolism than administration of PTH1-34 or R568 alone to (a) speed up structural and functional recovery of the bone subjected to a unilateral tibial mid-shaft fracture procedure and (b) to increase structural and mechanical strength of the contralateral bone in adult and aging mice. Aim 2: determine (a) whether the expression of chondrocytic CaSR is required for fracture healing and the anabolic effects of PTH1-34/R568 on promoting chondrocyte differentiation and their transition into OBs by testing the effects of chondrocyte-specific CaSR KO on the fractured calluses in the presence or absence of those drugs; and (b) whether the expression and activation of CaSRs in OBs and/or OCLs are essential for the osteoanabolic effects of the PTH1-34/R568 treatment by comparing the effects of this regimen on fractured and uninjured skeleton in mice with their CaSR ablated in OBs or OCLs, respectively. Aim 3 will delineate the cell-autonomous mechanisms underlying the effects of PTH1-34/R568 on the chondro-to-osteo transition by examining the effects of the compounds on the proliferation, survival, differentiation, mineralizing functions, and signaling responses in cultured callus chondrocytes lacking CaSR and/or PTH1R. Our preliminary studies showed that co-injections of intermittent PTH with a calcimimetic, NPS-R568, (i) prevent hypercalcemia, (ii) enhance anabolic effects on both trabecular and cortical bone, (iii) promote healing of tibial bone fractures, and (iv) enhance transdifferentiation of callus chondrocytes into osteoblasts in mice. Successful completion of this proposal will establish a novel and feasible regimen to rehabilitate fractured and osteoporotic bones in large populations of VA patients.

对于在军队中遭受创伤的退伍军人来说，骨折是一个重大问题 职责或作为平民流行的骨质疏松症。间歇（或每天）施用甲状旁腺 激素（PTH）是 FDA 批准的唯一一种能够产生骨合成代谢来治疗骨质疏松症的药物。 PTH 的骨合成代谢作用基于激素改变全身和局部因素的能力，这些因素 在刺激破骨细胞 (OCL) 活性赶上之前促进成骨细胞 (OB) 活性，从而产生 “合成代谢窗口”对骨量和结构产生积极影响，以恢复骨骼的机械完整性。 间歇性 PTH 也被证明可以促进骨折修复早期阶段老茧中的软骨形成 在临床前模型中。多项临床试验也证明了骨折时间歇性 PTH 的骨合成代谢作用 网站。然而，由于潜在的不利影响，其剂量仅限于低水平和短持续时间—— 高钙血症和骨肉瘤的诱发。我们的建议旨在描绘潜在的机制 骨合成代谢作用和 PTH 的高钙作用，以便制定增强 PTH 的新策略 治疗。提高 [Ca] 会激活软骨细胞和 OB 中的细胞外钙敏感受体 (CaSR) 促进其生存和分化，在 OCL 中抑制其生存和骨吸收功能。 我们假设间歇性 PTH 的高钙血症作用对于产生 骨合成代谢。一类变构CaSR激动剂（或拟钙剂）已在临床上用于治疗 通过增强细胞外 Ca 诱导的 PTH 分泌抑制来治疗甲状旁腺功能亢进和高钙血症 甲状旁腺细胞（PTC）。在这项新的拨款申请中，我们假设该化合物与 间歇性 PTH 不仅可以减轻 PTH 的高钙血症副作用，还可以协同其他药物的作用 PTH 并通过直接激活软骨细胞、OB 和 OCL 中的 CaSR 来增强骨骼合成代谢。我们 假设同时的拟钙剂治疗促进软骨向骨的转变，并且 通过激活软骨细胞、OB 中的 CaSR 来增强间歇性 PTH1-34 的骨合成代谢， 和/或 OCL 来提高骨折修复能力，同时修复其他弱化的部位 骷髅。目标 1 将确定是否同时激活 PTC、软骨细胞、OB 和 通过全身同时给予 R568 和 PTH1-34 进行 OCL 可消除高钙血症并产生更多 与单独使用 PTH1-34 或 R568 相比，骨合成代谢更强劲， (a) 加速结构和功能 进行单侧胫骨中轴骨折手术后的骨骼恢复，以及（b）增加结构性 以及成年和衰老小鼠对侧骨的机械强度。目标 2：确定 (a) 是否 软骨细胞 CaSR 的表达对于骨折愈合和 PTH1-34/R568 的合成代谢作用是必需的 通过测试软骨细胞特异性的作用，促进软骨细胞分化及其向 OB 的转变 在存在或不存在这些药物的情况下，CaSR KO 对骨折愈伤组织进行作用； (b) 表达式是否 OB 和/或 OCL 中 CaSR 的激活对于 PTH1-34/R568 的骨合成代谢作用至关重要 通过比较该方案对小鼠骨折和未受伤骨骼的效果及其 CaSR 进行治疗 分别在 OB 或 OCL 中消融。目标 3 将描述细胞自主机制 通过检查化合物对软骨到骨转变的影响，研究 PTH1-34/R568 对软骨到骨转变的影响 培养愈伤组织中的增殖、存活、分化、矿化功能和信号反应 缺乏 CaSR 和/或 PTH1R 的软骨细胞。我们的初步研究表明，间歇性联合注射 PTH 与拟钙剂 NPS-R568，(i) 预防高钙血症，(ii) 增强两者的合成代谢作用 小梁骨和皮质骨，(iii) 促进胫骨骨折愈合，(iv) 增强转分化 小鼠愈伤组织软骨细胞转化为成骨细胞。该提案的成功完成将建立一个新颖的 以及使大量 VA 患者骨折和骨质疏松骨骼康复的可行方案。