Mechanism of radiotherapy-induced osteoporosis and its treatment

 描述(申请人提供)：放射治疗通常用于清除肿瘤细胞，但会对包括骨骼在内的邻近正常组织产生不良影响，导致放射性骨坏死、骨质疏松和骨折等急性和慢性问题。在接受骨盆区放射治疗的患者中，骨折发生率的增加在临床上可能是显著的，骨盆骨折是老年人发病率和死亡率的重要原因。到目前为止，还没有临床证明的治疗这种毁灭性疾病的方法。骨骼健康和骨骼动态平衡需要持续的骨转换，包括平衡的骨形成和吸收。利用一个新的小动物辐射研究平台(SARRP)，我们最近建立了一个啮齿类动物的焦点辐射模型，该模型再现了放射治疗对骨骼造成的许多方面的损伤。对这一模型的详细分析表明，辐射通过显著和持续地减少成骨细胞系细胞的数量，包括成骨细胞及其间充质祖细胞，导致局部骨小梁丢失。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受照射骨的这种骨丢失和结构恶化，其主要机制似乎是通过刺激PKA/？-catenin途径来保护成骨细胞免受辐射诱导的细胞凋亡。辐射直接或间接地在细胞内产生大量DNA损伤，其中DNA双链断裂(DSB)是导致细胞死亡的最有害的损伤。机制研究表明，激活规范的Wnt/ç-catenin信号通路能够通过非同源末端连接途径促进DSB的修复，从而阻断辐射诱导的成骨细胞系细胞的凋亡。硬化素是一种骨细胞分泌的Wnt拮抗剂，其功能缺失突变会导致高骨量表型。抗硬化素抗体(scl-Ab)对骨小梁的辐射防护作用与甲状旁腺激素相同。最引人注目的是，在硬化素基因敲除小鼠中，辐射的损害效应被完全消除。我们推测，成骨细胞及其前体细胞的长期损伤，导致骨形成减少，是放射后骨恶化的主要原因，合成代谢单抗治疗是通过保护骨形成细胞免受凋亡而有效的骨损伤治疗方法。我们的目标是：1)明确临床相关局部放疗对骨、成骨细胞和间充质祖细胞的辐射损伤机制；2)表征局部放射治疗对骨、成骨细胞和间充质祖细胞的救援作用。 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作为辐射诱发的骨质疏松症的治疗方法的新用途提供原则证据，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疗法，使数百万癌症患者受益，这种疗法允许对肿瘤使用最大剂量的放射治疗，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.