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Novel therapy for osteoporosis

骨质疏松症的新疗法

基本信息

批准号：
7746723
负责人：
Emma E. Moore
金额：
$ 19.39万
依托单位：
OMEROS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7746723
关键词：
Affect Age Alkaline Phosphatase American Anabolic Agents Area Biological Assay Bone Diseases Bone Marrow Bone Resorption Bone remodeling Calcitonin Cartilage Cartilage Matrix Cattle Cell physiology Cells Chemistry Chondrocytes Collaborations Collagen Type I Degenerative polyarthritis Development Diabetes Mellitus Direct Expenditure Disease Disease Progression Disuse Atrophy Estrogens Evaluation Event Fracture Generations Glucocorticoids Goals Government Growth Factor Hip Fractures Homeostasis Impairment In Vitro Inflammatory Injection of therapeutic agent Insulin-Like Growth Factor I Interleukin-1 Lead Lesion Libraries Mediating Modeling Monitor Mus Natural regeneration Osteoblasts Osteocalcin Osteoclasts Osteogenesis Osteopenia Osteoporosis Ovariectomy Pathway interactions Persons Pharmaceutical Preparations Phase Phosphotransferases Postmenopausal Osteoporosis Process Production Publishing Recombinants Research Research Project Grants Research Proposals Screening procedure Selective Estrogen Receptor Modulators Signal Pathway Site Small Interfering RNA Specificity Spinal Fractures Structure Subcutaneous Injections Surveys System TNF gene Testing Therapeutic Agents Tumor Necrosis Factor Receptor Woman Work anakinra base bisphosphonate bone bone loss cytokine drug candidate high risk inhibitor/antagonist kinase inhibitor men mineralization novel novel therapeutic intervention novel therapeutics osteoblast differentiation osteogenic osteoprogenitor cell precursor cell prevent progenitor public health relevance receptor repaired response restoration small molecule tumor necrosis factor receptor 1A wrist fracture

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our research is to develop a novel treatment for osteoporosis that will stimulate bone formation. An estimated 10 million Americans over the age of 50 have osteoporosis, and another 34 million people are at high risk of developing this disease. One out of every two women and one in four men over 50 will have an osteoporosis-related fracture in their lifetime. Osteoporosis is responsible for more than 1.5 million fractures annually, including 300,000 hip fractures, approximately 700,000 vertebral fractures, 250,000 wrist fractures, and more than 300,000 fractures at other sites. Nationally, the estimated direct expenditures for osteoporosis and related fractures are $14 billion per year. Post-menopausal osteoporosis is characterized by an increased rate of bone remodeling; however, bone formation does not keep pace with increased bone resorption resulting in net loss of bone. Most current treatments for osteoporosis are directed at inhibiting increased bone resorption, and the only clinically available anabolic agent (PTH) is administered by injection and can only be used for 24 months. A key event in the development of post-menopausal osteoporosis is an increase in the levels of pro-inflammatory cytokines such as TNF and IL-1. These cytokines drive the production and activation of the bone resorptive cells and this process has been the focus of intensive research efforts. However, these cytokines have also been shown to inhibit bone formation, and this phenomenon is likely responsible for the uncoupling of bone formation and resorption that is ultimately responsible for bone loss that occurs in post-menopausal osteoporosis. Any agent that could reverse this inhibition would "re-couple" bone formation and resorption and thus provide a novel therapeutic approach for treatment of post-menopausal osteoporosis and other bone disorders that are characterized by impaired bone formation. Osteoarthritis (OA) is also characterized by a cytokine-driven increase in matrix turnover in which localized inhibition of anabolic processes results in the development of focal degenerative lesions. We have used an in vitro OA model to identify two small molecule kinase inhibitors, from over 100 that were screened, that completely reverse IL-1 or TNF inhibition of IGF-1 anabolic function. The primary target for these two inhibitors is the same; however, the fact that other inhibitors with the same specificity for that same target cannot restore the IGF-1 response indicates that a second novel target must be involved. One objective of this Phase I proposal is to determine whether the same subset of kinase inhibitors that are effective in the in vitro OA model will prevent the TNF-inhibition of osteoblast differentiation and/or restore the impaired osteogenic potential of bone marrow progenitors derived from ovariectomized mice. Secondly, a chemistry effort will be initiated to generate proprietary drug candidates by screening a panel of compounds selected for their structural similarity to our active inhibitors. PUBLIC HEALTH RELEVANCE: Osteoporosis affects an estimated 10 million Americans over the age of 50 and is responsible for more than 1.5 million fractures annually. We propose to develop a novel therapy for osteoporosis that will stimulate new bone formation.

描述（由申请人提供）：我们研究的长期目标是开发一种新的骨质疏松症治疗方法，刺激骨形成。据估计，有1000万50岁以上的美国人患有骨质疏松症，另有3400万人患这种疾病的风险很高。50岁以上的人群中，每两名女性中就有一名，每四名男性中就有一名会在一生中患上骨质疏松相关骨折。骨质疏松症每年造成150多万例骨折，包括30万例髋部骨折，大约70万例椎体骨折，25万例腕部骨折，以及30多万例其他部位骨折。在全国范围内，骨质疏松症和相关骨折的直接支出估计为每年140亿美元。绝经后骨质疏松症的特点是骨重塑率增加；然而，骨形成跟不上骨吸收的增加，导致骨的净损失。目前大多数骨质疏松症的治疗都是针对抑制骨吸收的增加，临床唯一可用的合成代谢剂（PTH）是通过注射给药，只能使用24个月。绝经后骨质疏松症发生的一个关键事件是促炎细胞因子如TNF和IL-1水平的增加。这些细胞因子驱动骨吸收细胞的产生和激活，这一过程一直是深入研究的重点。然而，这些细胞因子也被证明可以抑制骨形成，这种现象可能导致骨形成和骨吸收的分离，最终导致绝经后骨质疏松症中发生的骨质流失。任何能够逆转这种抑制作用的药物都将“重新耦合”骨形成和吸收，从而为治疗绝经后骨质疏松症和其他以骨形成受损为特征的骨疾病提供一种新的治疗方法。骨关节炎（OA）还以细胞因子驱动的基质周转增加为特征，其中合成代谢过程的局部抑制导致局灶性退行性病变的发展。我们使用体外OA模型从筛选的100多种小分子激酶抑制剂中鉴定出两种完全逆转IL-1或TNF抑制IGF-1合成代谢功能的小分子激酶抑制剂。这两种抑制剂的主要靶点是相同的；然而，对同一靶点具有相同特异性的其他抑制剂不能恢复IGF-1反应的事实表明，必须涉及第二个新靶点。这项I期研究的一个目的是确定在体外OA模型中有效的激酶抑制剂的同一亚群是否会阻止tnf对成骨细胞分化的抑制和/或恢复来自卵巢切除小鼠的骨髓祖细胞受损的成骨潜能。其次，将启动化学工作，通过筛选一组与活性抑制剂结构相似的化合物来产生专利候选药物。公共卫生相关性：骨质疏松症影响了大约1000万50岁以上的美国人，每年造成150多万例骨折。我们建议开发一种新的治疗骨质疏松症的方法，刺激新骨的形成。