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(由申请者提供)：该项目旨在确定成人骨髓细胞的变化对骨骼老化的贡献。衰老对人骨髓基质细胞向成骨细胞分化的影响对于了解增龄性骨丢失和骨质疏松症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，贴壁的人骨髓基质细胞(HMSCs)分化为碱性磷酸酶阳性(AlkP+)细胞的能力随着年龄的增加而降低。第一个特定的目的是验证以下假设：随着年龄的增长，骨髓基质细胞中Stro-1阳性(+)的比例减少，向AlkP+前成骨细胞的分化减少，体外三维成骨减少。这些减少很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。第二个特定目标测试假说，即随着年龄的增长，甲状旁腺激素(PTH)和性激素等骨合成代谢药物反应的信号转导减弱；第三个特定目标测试联合治疗是否可以逆转骨髓基质细胞向成骨细胞分化的年龄特异性下降。将评估增强的机制，重点是对IGF-1的调节和对细胞凋亡的调控。本课程将研究与年龄相关的信号和调节调节因子功能障碍。我们将确定hMSCs中是否存在与年龄相关的PTH信号下降，这是否涉及CREB 1和2通路，特定的化学抑制剂和/或通过siRNA技术敲除CREB是否会减少年轻个体hMSCs中的PTH信号，从而使IGF-I和成骨细胞生成减少到老年hMSCs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生成和骨形成。这些研究将提供关于骨髓基质细胞随年龄变化的有价值的信息，为恢复细胞生理学的新策略提供洞察力，从而改善成骨能力，并开始揭示这些药物促进老年个体细胞分化的机制。