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: 7259730
• 负责人: JULIANNE GLOWACKI
• 金额: $ 28.21万
• 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/7259730
• 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）：该项目旨在确定成年人类骨髓细胞变化有助于骨骼衰老的方式。衰老对成骨细胞与人骨髓基质细胞室分化的影响对于理解与年龄相关的骨质流失和骨质疏松症的机制和治疗至关重要。以前，我们在二维（2D）和三维（3D）模型系统中都发现，粘附的人骨髓基质细胞（HMSC）在分化与碱性磷酸酶阳性（ALKP+）细胞的能力下的能力下降。第一个特定的目的检验了骨髓基质细胞的stro-1阳性（+）部分随着年龄的增长而降低的假设，并且与ALKP+稳定性细胞的分化有所降低，并且体外3D骨形成降低。这些减少可能与脂肪细胞分化的增加有关。方法包括免疫分类和定量分子方法，以表征成骨细胞和脂肪细胞谱系。第二个特定目的测试了假设，随着衰老的响应，信号转导减少，响应于骨甲状腺功能亢进剂（例如甲状旁腺激素（PTH）和性激素）以及第三个特定目的测试是否会逆转骨骨髓细胞分离对稳定骨的骨骨髓细胞分离型的年龄降低是否会逆转，而组合治疗是否会逆转。将评估增强机制，重点是调节IGF-1和凋亡。将检查与年龄相关的信号传导和调节介质功能障碍。我们将确定一致性是否是HMSC中PTH信号与年龄相关的下降，这是否涉及CREB ​​1和2途径，是否涉及siRNA技术的特定化学抑制剂和/或CREB敲低是否降低了年轻个体的HMSC中的PTH信号，从而降低了IGF-I和Osteoblastosens的HMSC和Osteoblastensosis降低到HMSC中的水平。这项研究将量化来自老年和老年受试者的骨髓细胞的成骨细胞生成和骨形成。这些研究应提供有关骨髓基质细胞的年龄依赖性变化的宝贵信息，并为新颖的策略提供了重新培养细胞生理学的新策略，从而改善了成骨，并开始揭示这些药物可以促进老年人细胞中成骨细胞分化的机制。