EFFECTS OF AGE ON SIGNALING IN HUMAN OSTEOBLASTOGENESIS

年龄对人类成骨细胞发生信号传导的影响

• 批准号: 7390355
• 负责人: JULIANNE GLOWACKI
• 金额: $ 28.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7390355
• 关键词: Adipocytes; Adrenal Glands; Adult; Age; Age-Related Bone Loss; Aging; Alkaline Phosphatase; Anabolic Agents; Andropause; Apoptosis; Biological Assay; Biological Models; Bone Density; Bone Marrow; Bone Resorption; CREB1 gene; Cell Aging; Cell Differentiation process; Cell physiology; Cells; Chemicals; Devices; Doctor of Philosophy; Elderly; Equilibrium; Estradiol; Fracture; Frequencies; Functional disorder; Gonadal Steroid Hormones; Hormones; Human; In Vitro; Individual; Inflammatory; Insulin-Like Growth Factor I; Ions; Literature; Marrow; Measures; Mediating; Mediator of activation protein; Menopause; Methods; Modeling; Molecular; Numbers; Osteoblasts; Osteogenesis; Osteoporosis; Parathyroid Hormones; Pathway interactions; Regulation; Rejuvenation; Reporting; Research; Research Personnel; Resources; Signal Pathway; Signal Transduction; Skeletal system; Small Interfering RNA; Somatomedins; Somatotropin; Sorting - Cell Movement; Staging; Stanolone; Stromal Cells; System; Technology; Testing; Total Hip Replacement; Woman; adipocyte differentiation; age effect; age related; arthropathies; bone loss; cell age; dehydroepiandrosterone; experience; human PTH protein; improved; inhibitor/antagonist; insight; lipid biosynthesis; men; monolayer; novel; novel strategies; progenitor; programs; response; three-dimensional modeling; two-dimensional

DESCRIPTION (provided by applicant): This project seeks to identify the ways in which changes in the cells of adult human bone marrow contribute to skeletal aging. The effects of aging on osteoblast differentiation from the human bone marrow stromal cell compartment are of importance for understanding the mechanisms and treatment of age-related bone loss and osteoporosis. Previously, we found in both two-dimensional (2D) and in three-dimensional (3D) model systems that adherent human bone marrow stromal cells (hMSCs) undergo an age-dependent decrease in capacity for differentiation to alkaline phosphatase-positive (AlkP+) cells. The first specific aim tests the hypotheses that the STRO-1-positive (+) fraction of marrow stromal cells is decreased in frequency with age and that there a decrease in differentiation to AlkP+ pre-osteoblasts and decrease in 3D bone formation in vitro. These decreases are likely to be associated with an increase in adipocyte differentiation. Methods include immuno-sorting and quantitative molecular methods to characterize the osteoblast and adipocyte lineages. The second specific aim tests the hypotheses that with aging, there is diminished signal transduction in response to osteo-anabolic agents like parathyroid hormone (PTH) and sex hormones and the third specific aim tests whether combination treatments may reverse the age-specific decrease in bone marrow stromal cell differentiation to osteoblasts. The mechanism of enhancement will be assessed, with focus on regulation of IGF-1 and on apoptosis. Age-related dysfunction in signaling and regulatory mediators will be examined. We shall determine whether there is consistency is the age-related decline in PTH signaling in hMSCs, whether this involves CREB 1 and 2 pathways, whether specific chemical inhibitors and/or CREB knockdown by siRNA technology reduce PTH signaling in hMSCs from young individuals and thus decrease IGF-I and osteoblastogenesis to levels found in elder hMSCs. This research will quantify osteoblastogenesis and bone formation by marrow cells from young and old subjects. These studies should provide valuable information on the age-dependent changes in bone marrow stromal cells, provide insights into novel strategies for rejuvenation of cellular physiology leading to improved osteogenesis, and begin to reveal mechanisms whereby these agents can promote osteoblast differentiation in cells from aged individuals.

描述（由申请人提供）：该项目旨在确定成人骨髓细胞的变化对骨骼衰老的影响。衰老对人骨髓基质细胞向成骨细胞分化的影响对于了解年龄相关性骨丢失和骨质疏松的机制和治疗具有重要意义。以前，我们发现在二维（2D）和三维（3D）模型系统中，粘附的人骨髓基质细胞（hMSCs）分化为碱性磷酸酶阳性（AlkP+）细胞的能力经历了年龄依赖性下降。第一个具体目标检验了以下假设：骨髓基质细胞的STRO-1阳性（+）分数的频率随着年龄的增长而降低，并且在体外向AlkP+前成骨细胞的分化减少，并且3D骨形成减少。这些减少可能与脂肪细胞分化的增加有关。方法包括免疫分选和定量分子方法来表征成骨细胞和脂肪细胞谱系。第二个具体目标测试的假设，即随着年龄的增长，有减少的信号转导骨合成代谢剂，如甲状旁腺激素（PTH）和性激素和第三个具体目标测试联合治疗是否可以扭转骨髓基质细胞分化成骨细胞的年龄特异性下降。将评估增强的机制，重点是IGF-1的调节和细胞凋亡。将检查信号传导和调节介质中的神经元相关功能障碍。我们将确定是否存在hMSC中PTH信号的年龄相关性下降的一致性，这是否涉及CREB 1和2途径，是否特异性化学抑制剂和/或通过siRNA技术敲低CREB降低年轻个体的hMSC中的PTH信号，从而将IGF-I和成骨细胞生成降低到老年hMSC中发现的水平。这项研究将量化年轻和老年受试者骨髓细胞的成骨细胞和骨形成。这些研究应提供有价值的信息，骨髓基质细胞的年龄依赖性变化，提供洞察到新的战略振兴的细胞生理学导致改善成骨，并开始揭示机制，使这些代理商可以促进成骨细胞分化的细胞从老年人。