Center of Research Translation on Osteoporosis Bone Anabolic Therapies

项目概要-总体 骨质疏松症是我国人口老龄化的主要问题。虽然骨质疏松症的药物治疗 在过去的20年里，这种治疗方法有了很大的进步，可以真正降低骨折的风险， 年轻人的水平仍然难以捉摸。骨合成代谢治疗（甲状旁腺激素受体激动剂 特立帕肽/阿巴帕肽和抗硬化蛋白抗体罗莫珠单抗）代表了 我们治疗这种常见的，昂贵的，严重的，使人衰弱的疾病的医疗设备。没有 优化的能力，刺激骨形成，治愈骨质疏松症的许多患者严重的疾病将 无法实现。值得注意的是，我们目前使用的药物的合成代谢功效随着时间的推移而减弱， 原因CORT的目的是阐明骨质疏松症合成代谢疗法的作用机制， 理解他们为什么停止工作。在这样做的过程中，CORT将加速知识的翻译，以提高 我们对骨质疏松症病理学的理解。为了实现这一目标，CORT的总体重点是 确定目前使用的骨质疏松症合成代谢药物的细胞和分子作用机制， 人类一个高度协作的、多学科的、国际性的调查人员网络， 以哈佛医学院为基础的机构和帝国理工学院伦敦已经联合起来解决这个问题 挑战.在项目1中，研究者将确定romosozumab和teriparlitazone对骨骼干细胞的影响。 包括成骨细胞祖细胞在内的细胞，使用流式细胞术、单细胞RNA测序和组织病理学。 将使用来自接受合成代谢治疗的患者的样本进行研究，并补充 基因修饰的小鼠模型，其中谱系追踪和单细胞RNA测序可以结合。在 项目2，研究者将确定romosozumab和teriparlidine对骨细胞的影响。基于 初步数据显示，骨细胞可以直接调节骨基质的形成和重塑，导致令人兴奋的 假设，在人类和小鼠样本中测试，合成代谢剂通过直接作用于皮质骨， 对骨细胞的骨重建的影响。项目1和2将得到高度创新的 生物信息学核心，将跨物种转录组学数据集与可用的人类和 小鼠遗传学，以发展新的假设，也在这里测试，关于基因和基因网络 介导骨合成代谢反应。CORT的工作将进一步加强， 研究者在骨质疏松症临床研究、骨生物力学、骨干细胞生物学、 骨细胞生物学，骨髓微环境研究，统计遗传学，骨质疏松 流行病学和遗传起源的骨骼疾病。

Project Summary – Overall Osteoporosis is a major problem in our aging population. While the pharmacological treatment of osteoporosis has advanced substantially over the past 2 decades, treatment that can truly reduce the risks of fracture to youthful levels remains elusive. Bone anabolic therapies (parathyroid hormone receptor agonists teriparatide/abaloparatide and the anti-sclerostin antibody romosozumab) represent an important component of our therapeutic armamentarium for this common, costly, serious, and debilitating disease. Without an optimized ability to stimulate bone formation, cure of osteoporosis for many patients with severe disease will not be achieved. Notably, the anabolic efficacy of our currently-used agents wanes over time for unknown reasons. The goal of the CORT is to elucidate mechanisms of action of osteoporosis anabolic therapies, and to understand why they stop working. In doing so, the CORT will accelerate translation of knowledge to improve our understanding of osteoporosis pathobiology. To achieve this goal, the overall focus of the CORT is to define the cellular and molecular mechanisms of action of currently-used osteoporosis anabolic agents in humans. A highly-collaborative, multi-disciplinary, international network of investigators based at several Harvard Medical School-based institutions and Imperial College London have come together to tackle this challenge. In Project 1, investigators will define the effects of romosozumab and teriparatide on skeletal stem cells including osteoblast progenitors using flow cytometry, single cell RNA sequencing, and histopathology. Studies will be performed using samples from patients receiving anabolic therapy and in complementary genetically-modified mouse models where lineage tracing and single cell RNA sequencing can be combined. In Project 2, investigators will define the effects of romosozumab and teriparatide on osteocytes. Based on preliminary data, osteocytes can directly regulate bone matrix formation and remodeling, leading to the exciting hypothesis, tested here in human and mouse samples that anabolic agents impact cortical bone via direct effects on osteocytic perilacunar remodeling. Projects 1 and 2 will be supported by a highly innovative Bioinformatics Core that will incorporate cross-species transcriptomics datasets with available human and mouse genetics in order to develop novel hypotheses, also tested here, regarding genes and gene network that mediate bone anabolic responses. CORT efforts will be further enhanced by the complementary experience of investigators in osteoporosis clinical research, bone biomechanics, bone stem cell biology, osteocyte biology, bone marrow microenvironment investigation, statistical genetics, osteoporosis epidemiology, and genetic origins of bone disease.