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Actions of Endoxifen on the Skeleton

恩多昔芬对骨骼的作用

基本信息

批准号：
8398792
负责人：
Anne Gingery
金额：
$ 5.57万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-18 至 2015-07-17
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8398792
关键词：
Anabolic Agents Animals Biological Models Biology Bone Resorption Bone remodeling Calcitonin Data Development Disease Dose Endocrine Estrogen Analogues Estrogens Exhibits Fellowship Fracture Gene Expression Generations Goals Innate Bone Remodeling Knowledge Laboratories Lead Literature Malignant Neoplasms Mesenchymal Differentiation Molecular Mus Osteoblasts Osteoclasts Osteogenesis Osteopenia Osteoporosis Osteoporosis prevention Pharmaceutical Preparations Postdoctoral Fellow Raloxifene Reporting Research Research Personnel Risk Selective Estrogen Receptor Modulators Signal Transduction Skeleton Societies Structure Tamoxifen Techniques Testing Therapeutic Therapeutic Agents Time Training bisphosphonate bone bone cell bone health bone loss bone mass bone metabolism bone quality bone turnover cancer initiation cancer therapy career career development experience in vivo malignant breast neoplasm mouse model nanoindentation novel osteoblast differentiation prevent progenitor response skeletal skills spine bone structure therapeutic development tomography tumor progression

项目摘要

DESCRIPTION (provided by applicant): Currently there is no cure for osteoporosis and the development of therapeutic treatments remains limited. Present day therapies involve anti-resorptive agents such as bisphosphonates, estrogen analogs, raloxifene and calcitonin which primarily target bone resorbing osteoclasts resulting in reduced bone turnover. However anti-resorptive therapies are not associated with significant increases in bone mass and therefore only partially reduce fracture risk and prevent the normal bone remodeling required to maintain bone health. Thus, a significant need exists for the development of additional bone anabolic agents to prevent or treat this debilitating disease. This project explores the actions of endoxifen, a tamoxifen metabolite, on the skeleton and its mechanism of action in bone cells. Preliminary data suggests that endoxifen increases quality and structure of bone in conditions of reduced estrogen as is seen in osteoporosis and may be more favorable than other new generation breast cancer therapies which exhibit significant deleterious skeletal effects. Therefore, the central hypothesis is that endoxifen, a novel SERM, elicits bone anabolic effects by increasing, rather than decreasing, bone formation thereby functioning differently than that of other SERMs. The goals of this proposal are to characterize in vivo effects on the skeleton using a mouse model system and to identify the molecular mechanisms by which endoxifen, as compared to tamoxifen and raloxifene, exerts its effects on cultured osteoblasts, and osteoclasts. PUBLIC HEALTH RELEVANCE: Osteoporosis and Breast Cancer are major burdens on society. Endoxifen is a newly identified as the primary active metabolite of Tamoxifen, one of the major therapeutic selective estrogen receptor modulators used in Breast Cancer therapy today. My preliminary studies have shown that Endoxifen is also a potent anabolic agent on the skeleton. Similar to Estrogen action on bone remodeling, my studies have indicated that Endoxifen maintains/enhances overall bone formation via enhanced remodeling. These studies have the potential to identify Endoxifen as a novel, highly beneficial, therapeutic agent for osteopenia, osteoporosis and other bone related disorders, as well as breast cancer therapy

描述（由申请人提供）：目前还没有治愈骨质疏松症的方法，治疗方法的发展仍然有限。目前的治疗方法包括抗骨吸收剂，如双膦酸盐、雌激素类似物、雷洛昔芬和降钙素，它们主要针对骨吸收破骨细胞，导致骨转换减少。然而，抗骨吸收治疗与骨量的显著增加无关，因此只能部分降低骨折风险并阻止维持骨骼健康所需的正常骨重塑。因此，迫切需要开发额外的骨合成代谢剂来预防或治疗这种使人衰弱的疾病。本项目探讨了他莫昔芬代谢物endoxifen对骨骼的作用及其在骨细胞中的作用机制。初步数据表明，在骨质疏松症中，内氧芬可以在雌激素减少的情况下提高骨骼质量和结构，可能比其他新一代乳腺癌治疗方法更有利，这些治疗方法对骨骼有明显的有害影响。因此，中心假设是内毒素，一种新型SERM，通过增加而不是减少骨形成，从而引起骨合成代谢作用，从而不同于其他SERM的功能。本提案的目标是利用小鼠模型系统表征对骨骼的体内影响，并确定与他莫昔芬和雷洛昔芬相比，内多西芬对培养的成骨细胞和破骨细胞施加影响的分子机制。