Mechanisms of Age-Related Skeletal Resistance to BMP-7 and IGF-I

年龄相关骨骼对 BMP-7 和 IGF-I 的抵抗机制

• 批准号: 8113119
• 负责人: MARTIN L ADAMO
• 金额: $ 6.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113119
• 关键词: Age-Related Bone Loss; Aging; Anabolic Agents; Animals; Attenuated; Bone Marrow; Bone Morphogenetic Proteins; Cell Aging; Cell Culture Techniques; Cells; Data; Development; Fracture; Future; Goals; Impairment; Insulin-Like Growth Factor I; Lead; Mediating; Molecular; Morbidity - disease rate; Mus; Osteogenesis; Osteoporosis; Outcome; Pathway interactions; Phosphorylation; Population; Property; Protein Isoforms; Protein Kinase C; Publishing; RNA Interference; Research Design; Resistance; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Skeleton; Stromal Cells; System; Testing; Therapeutic; Therapeutic Agents; Translating; Wild Type Mouse; Work; age related; aged; attenuation; base; bone; bone morphogenetic protein 2; bone morphogenetic protein 7; cell age; clinical application; in vivo; male; novel therapeutics; osteoblast differentiation; osteoprogenitor cell; receptor; response; skeletal; success

DESCRIPTION (provided by applicant): Bone Morphogenetic proteins (BMPs) show great promise as bone anabolic agents in several therapeutic settings. One of the most important potential clinical applications is in the treatment of age-related osteoporosis. However, the utility of BMP treatment of age-related osteoporosis and related fractures may be limited by resistance to the bone forming actions of BMPs in the aged skeleton. Thus, understanding the mechanisms of age-related resistance to BMPs is critical to the success of strategies aimed at restoring sensitivity and/or overcoming resistance to bone anabolic action in the aged. Our work and that of others indicates that BMP-2 and BMP-7, the two most widely studied BMPs, stimulate osteoblastic differentiation by activating IGF-1 signaling pathways. However, studies also indicated that osteoprogenitor cells from aged animals may be resistant to the bone anabolic effects of IGF-1 due to reduced IGF-1 stimulated IGF-1 receptor phosphorylation and reduced activation of downstream signaling pathways including PI3K/Akt and ERK. We and others have found that BMP signaling via the PKC isoform PKD may be a component in the IGF-1 signaling pathway that stimulates osteoblastic differentiation. Based on our preliminary studies indicating that bone marrow stromal cells (BMSC) from aged wild-type mice and from young and old IGF-1 receptor heterozygous mice may be resistant to BMP-7, we hypothesize that BMSC from aged mice are resistant to BMP-7 activation of PI3K/Akt/PKD signaling and possibly other IGF-1 signaling pathways. We propose to test this hypothesis by first comprehensively examining the IGF-1R, PI3K/Akt/PKD and ERK pathways for resistance to BMP-7 activation in BMSC from aged mice. We will critically test the hypothesis that resistance of these pathways to BMP-7 stimulation underlies the resistance of BMSC to the differentiating effect of BMP-7 by conducting RNA silencing of the IGF-1R in cells from young wild-type mice and by expressing constitutively active forms of the IGF-1R and downstream effector molecules in cells from aged wild-type and young and aged Igf1r mice and determining whether they can inhibit and promote osteoblastic differentiation, respectively. In our second specific aim we will translate these findings to the in-vivo setting by determining whether young IGF-1 receptor heterozygous mice and old wild-type mice are resistant to the ectopic bone forming action of BMP-7. We will also determine whether IGF-1 receptor haplo-insufficiency exacerbates age-related resistance to BMP-7 induced bone formation. Successful outcomes will provide the basis for future studies designed to rescue in vivo age-related resistance to BMPs by expressing active forms of IGF-1 signaling intermediates. These results could lead to the development of new therapeutic modes for treating osteoporosis. PUBLIC HEALTH RELEVANCE: Age related osteoporosis is a major cause of debilitation and morbidity in the gerontological population. The goal of the current study is to provide a molecular basis for the development of novel therapeutic agents that will treat age related osteoporosis by activating signal transduction pathways used by bone anabolic agents.

描述（由申请人提供）：骨形态发生蛋白（BMP）在几种治疗环境中显示出作为骨合成代谢剂的巨大前景。最重要的潜在临床应用之一是治疗与年龄相关的骨质疏松症。然而，BMP治疗与年龄相关的骨质疏松症和相关骨折的效用可能受到对BMP在老年骨骼中的骨形成作用的抵抗的限制。因此，了解与年龄相关的骨形成蛋白抵抗的机制对于旨在恢复老年人对骨合成代谢作用的敏感性和/或克服抵抗的策略的成功至关重要。我们的工作和其他人的工作表明，BMP-2和BMP-7，这两种最广泛研究的BMP，通过激活IGF-1信号通路刺激成骨细胞分化。然而，研究还表明，来自老年动物的骨祖细胞可能对IGF-1的骨合成代谢作用具有抗性，这是由于IGF-1刺激的IGF-1受体磷酸化减少以及下游信号通路（包括PI 3 K/Akt和ERK）的活化减少。我们和其他人已经发现，通过PKC亚型PKD的BMP信号传导可能是IGF-1信号通路中刺激成骨细胞分化的一个组成部分。基于我们的初步研究表明，来自老年野生型小鼠和来自年轻和老年IGF-1受体杂合小鼠的骨髓基质细胞（BMSC）可能对BMP-7具有抗性，我们假设来自老年小鼠的BMSC对BMP-7激活PI 3 K/Akt/PKD信号传导和可能的其他IGF-1信号传导途径具有抗性。我们建议通过首先全面检查IGF-1 R，PI 3 K/Akt/PKD和ERK通路对老年小鼠BMSC中BMP-7活化的抗性来验证这一假设。我们将通过在来自年轻野生型小鼠的细胞中进行IGF-1 R的RNA沉默和通过在来自老年野生型小鼠的细胞中表达组成型活性形式的IGF-1 R和下游效应分子，来严格检验这些途径对BMP-7刺激的抗性是BMSC对BMP-7分化效应的抗性的基础这一假设。型和青年及老年Igf 1 r小鼠，并分别测定它们是否能抑制和促进成骨细胞分化。在我们的第二个具体目标中，我们将通过确定年轻的IGF-1受体杂合小鼠和年老的野生型小鼠是否对BMP-7的异位骨形成作用具有抗性，将这些发现转化为体内环境。我们还将确定IGF-1受体单倍不足是否会加剧年龄相关的BMP-7诱导骨形成的阻力。成功的结果将为未来的研究提供基础，这些研究旨在通过表达IGF-1信号中间体的活性形式来挽救体内年龄相关的BMP抗性。这些结果可能导致新的治疗模式的发展，用于治疗骨质疏松症。 公共卫生相关性：年龄相关性骨质疏松症是老年人群衰弱和发病的主要原因。本研究的目的是为开发新的治疗药物提供分子基础，这些药物将通过激活骨合成代谢药物所使用的信号转导途径来治疗年龄相关性骨质疏松症。