Mechanism of radiotherapy-induced osteoporosis and its treatment

放疗引起骨质疏松的机制及治疗

• 批准号: 8964347
• 负责人: Ling Qin
• 金额: $ 35.95万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8964347
• 关键词: Acute; Address; Adverse effects; Animals; Antibodies; Apoptosis; Area; Blood Vessels; Bone Diseases; Bone Resorption; Cancer Patient; Cell Death; Cell Lineage; Cells; Cellularity; Chronic; Clinical Trials; Cyclic AMP-Dependent Protein Kinases; DNA Double Strand Break; DNA Repair; DNA lesion; Data; Deterioration; Disease; Dose; Elderly; Equilibrium; Fracture; G22P1 gene; Goals; Histology; Homeostasis; Hormones; Impairment; Incidence; Injection of therapeutic agent; Knockout Mice; Lead; Marrow; Mechanics; Mediating; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Nonhomologous DNA End Joining; Normal tissue morphology; Nuclear Protein; Obesity; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoradionecrosis; Pain; Parathyroid gland; Pathway interactions; Patients; Pelvis; Phenotype; Postmenopausal Osteoporosis; Prevention; Preventive; Radiation; Radiation Induced DNA Damage; Radiation induced damage; Radiation therapy; Radioprotection; Regimen; Reporter; Research; Risk; Rodent; Role; Scanning; Signal Transduction; Skeleton; Structure; Testing; Therapeutic; Time; Translating; Treatment Protocols; base; beta catenin; bone; bone health; bone loss; bone mass; bone turnover; cancer therapy; clinically relevant; clinically significant; effective therapy; in vivo; loss of function mutation; mortality; mouse model; neoplastic cell; novel; prevent; progenitor; public health relevance; radiation effect; repaired; skeletal; substantia spongiosa; tumor

 DESCRIPTION (provided by applicant): Radiotherapy is often used to eliminate tumor cells but can have untoward effects on neighboring normal tissues including bone, causing acute and chronic problems such as osteoradionecrosis, osteoporosis and fractures. In patients receiving radiotherapy in the pelvic region, the increased fracture incidence can be clinically significant, and pelvic fractures are a substantial cause of morbidity and mortality in the elderly. To date, there is no clinically proven treatment for this devastating disease. Bone health and skeletal homeostasis require constant bone turnover consisting of balanced bone formation and resorption. Using a newly available Small Animal Radiation Research Platform (SARRP), we recently established a rodent focal radiation model that reproduces many aspects of radiotherapy-induced damage on bone. Detailed analyses of this model demonstrated that radiation causes local trabecular bone loss by drastically and persistently reducing the number of osteoblast lineage cells, including osteoblasts and their mesenchymal progenitors. We initially found that daily injections of parathyroid hormone (PTH) largely prevented such bone loss and structural deterioration in irradiated bone and that the major mechanism appears to be the protection of osteoblasts from radiation- induced apoptosis via stimulating the PKA/ß-catenin pathway. Radiation exposure directly or indirectly generates a large amount of DNA lesions in cells, among which DNA double strand break (DSB) is the most deleterious one that causes cell death. Mechanistic studies showed that activating the canonical Wnt/ß-catenin signaling is capable of blocking radiation-induced apoptosis in osteoblast lineage cells by enhancing the repair of DSBs through a non-homologous end-joining pathway. Sclerostin is an osteocyte-secreted Wnt antagonist whose loss-of-function mutations lead to a high bone mass phenotype. Administration of antibody against sclerostin (Scl-Ab) elicited the same robust radioprotective actions on trabecular bone as PTH. Most strikingly, the damaging effects of radiation were completely abrogated in sclerostin knockout mice. We hypothesize that prolonged impairment of osteoblasts and their progenitors, which results in diminished bone formation, is a major cause of post-radiation bone deterioration and that anabolic Scl-Ab treatment is an effective therapy for radiation damage on bone by protecting bone-forming cells from apoptosis. Our aims are to: 1) define the mechanism for radiation damage on bone, osteoblasts, and mesenchymal progenitors caused by clinically relevant focal radiotherapy; 2) characterize the rescue effects of Scl-Ab on radiation-induced damage on bone; 3) uncover the mechanism by which Scl-Ab preserves osteoblasts and their progenitors. This project will provide proof-of-principle evidence for a novel use of Scl-Ab as a therapeutic treatment for radiation-induced osteoporosis and establish molecular and cellular mechanisms that support such treatment. Our long-term goal is to benefit millions of cancer patients by developing a therapy that allows the use of maximal radiotherapy doses on tumors while at the same time prevents the potentially severe bone-associated side effects.

 描述（由申请人提供）：放射治疗通常用于消除肿瘤细胞，但可能对包括骨骼在内的邻近正常组织产生不良影响，导致骨盆区域接受放射治疗的患者出现急性和慢性问题，例如放射性骨坏死、骨质疏松和骨折。骨折发生率的增加可能具有临床意义，并且骨盆骨折是老年人发病和死亡的主要原因，迄今为止，尚无临床证明可以治疗这种破坏性骨骼健康的疾病。骨骼稳态需要持续的骨转换，包括平衡的骨形成和骨吸收，我们最近使用新推出的小动物辐射研究平台（SARRP）建立了啮齿动物局灶辐射模型，该模型再现了放射治疗引起的骨损伤的许多方面。该模型证明，辐射通过急性和持续减少成骨细胞及其间质祖细胞的数量而导致局部骨小梁丢失。甲状旁腺激素 (PTH) 在很大程度上防止了受辐射骨骼中的骨质流失和结构恶化，其主要机制似乎是通过刺激 PKA/β-连环蛋白途径来保护成骨细胞免受辐射诱导的细胞凋亡。细胞中存在大量 DNA 损伤，其中 DNA 双链断裂 (DSB) 是导致细胞死亡的最有害的一种。机制研究表明，激活经典 Wnt/ß-catenin 信号传导是导致细胞死亡的原因。 Sclerostin 是一种骨细胞分泌的 Wnt 拮抗剂，其功能丧失突变可导致高骨量表型，从而通过非同源末端连接途径增强 DSB 的修复，从而阻止辐射诱导的成骨细胞凋亡。施用抗硬化素抗体 (Scl-Ab) 对骨小梁具有与 PTH 相同的强大放射防护作用，最引人注目的是，辐射的破坏作用在体内完全消除。我们发现，成骨细胞及其祖细胞的长期损伤会导致骨形成减少，这是辐射后骨质恶化的主要原因，而合成代谢 Scl-Ab 治疗是通过保护骨骼辐射损伤的有效疗法。我们的目标是：1) 确定临床相关的局部放疗对骨、成骨细胞和间质祖细胞造成辐射损伤的机制；描述救援效果 Scl-Ab 对辐射引起的骨损伤的影响；3) 揭示 Scl-Ab 保护成骨细胞及其祖细胞的机制。该项目将为 Scl-Ab 作为治疗方法的新用途提供原理证明证据。我们的长期目标是通过开发一种疗法，允许对肿瘤使用最大放射治疗剂量，同时预防癌症的发生，从而使数以百万计的癌症患者受益。潜在的严重的骨相关副作用。