Center of Research Translation on Osteoporosis Bone Anabolic Therapies

项目摘要--总体 骨质疏松症是我们老龄化人口中的一个主要问题。而骨质疏松症的药物治疗 在过去的20年里有了很大的进步，治疗可以真正降低骨折的风险 年轻的水平仍然难以捉摸。骨合成代谢疗法(甲状旁腺激素受体激动剂 Teriparatide/abaloparatide和抗硬化素抗体romosozumab)是 我们治疗这种常见、昂贵、严重且使人虚弱的疾病的医疗设备。如果没有一个 优化能力刺激骨形成，治愈许多严重疾病患者的骨质疏松症 不会实现的。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，这是未知的。 理由。CORT的目标是阐明骨质疏松症合成代谢疗法的作用机制，并 理解他们停止工作的原因。在这样做的过程中，CORT将加速知识的转化以改进 我们对骨质疏松症病理生物学的理解。为了实现这一目标，CORT的总体重点是 明确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、多学科的国际调查网络，总部设在几个 总部设在哈佛医学院的机构和伦敦帝国理工学院已经联手解决这一问题 挑战。在项目1中，研究人员将确定romosozumab和teriparatide对骨骼干的影响 应用流式细胞术、单细胞RNA测序和组织病理学检测细胞包括成骨细胞前体细胞。 研究将使用接受合成代谢治疗的患者的样本进行，并进行补充 基因改造的小鼠模型，其中谱系追踪和单细胞RNA测序可以结合起来。在……里面 项目2，研究人员将确定romosozumab和teriparatide对骨细胞的影响。基于 初步资料表明，骨细胞可以直接调节骨基质的形成和重塑，导致兴奋 假说，在人类和小鼠样本中验证，合成代谢剂通过直接作用于皮质骨 对骨细胞性楔周重塑的影响。项目1和2将由高度创新的 生物信息学核心，将跨物种转录组数据集与可用的人类和 小鼠遗传学，以开发新的假说，也在这里测试，关于基因和基因网络 调节骨骼合成代谢反应的物质。CORT的努力将进一步得到补充 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、骨髓微环境调查、统计遗传学、骨质疏松症 流行病学和骨病的遗传起源。

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.