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: 8243515
• 负责人: MARTIN L ADAMO
• 金额: $ 6.11万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243515
• 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; public health relevance; 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）：在几种治疗环境中，骨形态发生蛋白（BMP）作为骨合成代谢剂表现出巨大的希望。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。但是，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老年骨骼中BMP的骨骼形成作用的抗性的限制。因此，了解与年龄相关的BMP的抗性机制对于旨在恢复老年人骨合代代谢作用的敏感性和/或克服抗抗药性的策略的成功至关重要。我们的工作以及其他的工作表明，研究了两个最广泛研究的BMP的BMP-2和BMP-7通过激活IGF-1信号通路来刺激成骨细胞分化。然而，研究还表明，由于IGF-1刺激的IGF-1受体磷酸化减少以及包括PI3K/AKT和ERK在内的下游信号通路的激活，来自老年动物的骨基因细胞可能对IGF-1的骨合成代谢作用有抵抗力。我们和其他人发现，通过PKC同工型PKD的BMP信号传导可能是IGF-1信号传导途径中刺激成骨细胞分化的组件。基于我们的初步研究，表明来自老年野生型小鼠的骨髓基质细胞（BMSC）以及来自年轻和老式的IGF-1受体杂合小鼠可能对BMP-7具有抵抗力，我们假设来自年龄小鼠的BMSC对BMP-7的PIGFIG/akt/akt/akt/akt/pkt and-akt/pkt and tocigation and ocig and-pkd and-pkd and tocigation。我们建议通过首先全面检查IGF-1R，PI3K/AKT/PKD和ERK途径来检验这一假设，以抗老年小鼠BMSC中BMP-7激活的抗性。我们将批判性地检验以下假说：这些途径对BMP-7刺激的抗性是BMSC通过对年轻野生型小鼠的细胞中IGF-1R的RNA沉默和通过在IGF-1R和下型野生型生物效应的强度表达IGF-1R中的IGF-1R的耐药性来构成BMSC对BMP-7的区分作用的基础。 IGF1R小鼠并确定它们是否可以抑制和促进成骨细胞分化。在我们的第二个特定目的中，我们将通过确定年轻的IGF-1受体杂合小鼠和旧野生型小鼠是否对BMP-7的异位骨形成作用有抵抗力，将这些发现转化为体内环境。我们还将确定IGF-1受体的单倍不使人对BMP-7诱导的骨形成的年龄相关性是否加剧了与年龄相关的抗性。成功的结果将为未来的研究提供基础，旨在通过表达IGF-1信号中间体的主动形式来挽救与体内年龄相关的BMP的抗性。这些结果可能导致发展用于治疗骨质疏松症的新治疗模式。 公共卫生相关性：与年龄相关的骨质疏松症是老年医学人群中衰弱和发病率的主要原因。当前研究的目的是为开发新型治疗剂的发展提供分子基础，这些治疗剂将通过激活骨合代代理使用的信号转导途径来治疗与年龄相关的骨质疏松症。