Mechanism of radiotherapy-induced osteoporosis and its treatment

 描述（由申请人提供）：放射治疗通常用于消除肿瘤细胞，但可能对邻近的正常组织（包括骨）产生不良影响，导致急性和慢性问题，如放射性骨坏死、骨质疏松症和骨折。在骨盆区域接受放射治疗的患者中，骨折发生率的增加可能具有临床意义，骨盆骨折是老年人发病率和死亡率的重要原因。迄今为止，还没有临床证明的治疗这种毁灭性疾病的方法。骨健康和骨骼稳态需要恒定的骨转换，包括平衡的骨形成和吸收。使用新的小动物放射研究平台（SARRP），我们最近建立了一个啮齿动物局灶性放射模型，再现了放射治疗引起的骨损伤的许多方面。对该模型的详细分析表明，辐射通过急剧和持续减少成骨细胞谱系细胞（包括成骨细胞及其间充质祖细胞）的数量导致局部小梁骨丢失。我们最初发现，每天注射甲状旁腺激素（PTH）在很大程度上防止了辐射骨中的这种骨丢失和结构退化，并且主要机制似乎是通过刺激PKA/β-连环蛋白途径保护成骨细胞免受辐射诱导的凋亡。辐射直接或间接地使细胞DNA产生大量损伤，其中DNA双链断裂（DSB）是最有害的损伤，可导致细胞死亡。机制研究表明，激活经典的Wnt/β-连环蛋白信号传导能够通过非同源末端连接途径增强DSB的修复来阻断成骨细胞谱系细胞中辐射诱导的细胞凋亡。Sclerostin是一种骨细胞分泌的Wnt拮抗剂，其功能丧失突变导致高骨量表型。抗硬化蛋白抗体（Scl-Ab）的管理引起了相同的强大的辐射防护作用，骨小梁作为PTH。最引人注目的是，辐射的破坏作用在sclerostin敲除小鼠中完全消失。我们假设成骨细胞及其祖细胞的长期损伤导致骨形成减少，是辐射后骨退化的主要原因，合成代谢Scl-Ab治疗是通过保护骨形成细胞免于凋亡来治疗骨辐射损伤的有效疗法。我们的目标是：1）确定临床相关局灶性放疗对骨、成骨细胞和间充质祖细胞造成辐射损伤的机制; 2）表征 Scl-Ab对放射性骨损伤的保护作用; 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作为辐射诱导的骨质疏松症的治疗性治疗的新用途提供原理证明证据，并建立支持这种治疗的分子和细胞机制。我们的长期目标是通过开发一种治疗方法，使数百万癌症患者受益，该治疗方法允许对肿瘤使用最大放射治疗剂量，同时防止潜在的严重骨相关副作用。

 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.