Effect of Aging & Vitamin D Status on Osteoblastogenesis

老化的影响

• 批准号: 7475143
• 负责人: JULIANNE GLOWACKI
• 金额: $ 39.98万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475143
• 关键词: Address; Adherent Culture; Age; Aging; Apoptosis; Biochemical; Biological Assay; Bone Density; Bone Marrow; Bone Resorption; Cell physiology; Cells; Cultured Cells; Dihydroxycholecalciferols; Doctor of Philosophy; Elderly; Equilibrium; Fracture; Goals; Hematopoietic; Human; In Vitro; Individual Differences; Inflammatory; Literature; Marrow; Measures; Mediator of activation protein; Methods; Molecular; Numbers; Osteoblasts; Osteogenesis; Osteoporosis; Property; Regulation; Reporting; Research; Skeletal system; Sorting - Cell Movement; Stem cells; Stromal Cells; System; Techniques; Testing; Tissue Donors; Total Hip Replacement; Vitamin D; Vitamin D Deficiency; Woman; age effect; age related; analog; arthropathies; bone loss; experience; improved; innovation; men; paricalcitol; precursor cell; progenitor; stem; transcription factor

DESCRIPTION (provided by applicant): This application addresses two of the goals of the RFA: Use "of in vitro methods to assay stem cell function that reflect individual differences among cell or tissue donors" and "Potential systemic effects of age-related alterations in stem and precursor cell properties in specific lineages." Skeletal aging is characterized as a gradual loss of bone mass due to an excess of bone resorption that is not balanced by new bone formation. Thus, with age, there is a gradual loss of bone measured by declining bone mineral density (BMD), to the point of osteopenia or osteoporosis, and bone fracture. Bone marrow becomes fatty and ultimately "gelatinized" with extreme age and osteoporosis. In addition, elderly people commonly have lower circulating levels of 25-dihydroxyvitamin D (25-D). Marrow stromal cells (MSCs) give rise to osteoblasts, but there is some discrepancy in the literature about the effect of age on osteoblast differentiation. We, and others, reported that there is an age-related decline in osteoblastogenesis from human bone marrow. Some others, using colony assays, report no detectable change. We have been applying an innovative automated cell tracking system developed by Dr. Greenberger for hematopoietic cells for research in skeletal aging. We have extensive experience with human marrow obtained from subjects undergoing total hip replacement for non-inflammatory joint disease. We have developed a research plan with 3 specific aims to test the hypotheses 1) that with aging there is a loss of osteoblast potential in human marrow stromal cells from men and women; 2) that vitamin D-deficiency reduces osteoblast potential, and 3) that cells from elders and vitamin D-deficient subjects can be rejuvenated in vitro by vitamin D metabolites or analogs. We will use biochemical and molecular methods to enumerate and characterize MSCs with osteoblast potential. We propose to use an innovative quantitative cell tracking system to measure differentiation as a function of age of human marrow. We will also use monolayer culture methods to assess the effects of age on progress in osteoblast differentiation. We will determine whether vitamin D metabolites or analogs promote osteoblast differentiation of marrow cells and whether the mechanisms involve increasing numbers of progenitors, changes in proliferation and apoptosis, and/or stimulation of osteoblast differentiation.

描述（由申请人提供）：该申请解决了RFA的两个目标：使用“体外方法来测定反映细胞或组织供体个体差异的干细胞功能”和“特定谱系中干细胞和前体细胞特性的年龄相关改变的潜在系统影响”。骨骼老化的特点是骨量的逐渐损失，由于过量的骨吸收，不平衡的新骨形成。因此，随着年龄的增长，骨质逐渐流失，骨密度（BMD）下降，达到骨质减少或骨质疏松和骨折的程度。随着年龄的增长和骨质疏松，骨髓变得脂肪化，最终“糊化”。此外，老年人体内25-二羟基维生素D （25-D）的循环水平通常较低。骨髓基质细胞（MSCs）可分化成骨细胞，但文献中关于年龄对成骨细胞分化的影响存在一定的差异。我们和其他人报道了人类骨髓中成骨细胞发生与年龄相关的下降。其他一些人，使用菌落测定，报告没有可检测到的变化。我们一直在应用格林伯格博士开发的一种创新的自动细胞跟踪系统，用于研究骨骼老化的造血细胞。我们有丰富的经验，从接受全髋关节置换术治疗非炎症性关节疾病的受试者中获取人类骨髓。我们制定了一项研究计划，有三个具体目标来验证以下假设：1)随着年龄的增长，男性和女性的人类骨髓基质细胞中成骨潜能的丧失；2)维生素D缺乏会降低成骨潜能，3)老年人和维生素D缺乏者的细胞可以通过维生素D代谢物或类似物在体外恢复活力。我们将使用生化和分子方法枚举和表征具有成骨潜能的间充质干细胞。我们建议使用一种创新的定量细胞跟踪系统来测量分化作为人类骨髓年龄的函数。我们还将使用单层培养方法来评估年龄对成骨细胞分化进程的影响。我们将确定维生素D代谢物或类似物是否促进骨髓细胞的成骨细胞分化，以及其机制是否涉及祖细胞数量的增加、增殖和凋亡的变化和/或成骨细胞分化的刺激。

项目成果

Effects of age and gender on WNT gene expression in human bone marrow stromal cells.

• DOI: 10.1002/jcb.22010
• 发表时间: 2009-02-01
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Shen, Longxiang;Zhou, Shuanhu;Glowacki, Julie
• 通讯作者: Glowacki, Julie

Effect of age on regulation of human osteoclast differentiation.

• DOI: 10.1002/jcb.24792
• 发表时间: 2014-08
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Chung, Ping-Lin;Zhou, Shuanhu;Eslami, Behnam;Shen, Longxiang;LeBoff, Meryl S.;Glowacki, Julie
• 通讯作者: Glowacki, Julie

TGF-β regulates β-catenin signaling and osteoblast differentiation in human mesenchymal stem cells.

• DOI: 10.1002/jcb.23079
• 发表时间: 2011-06
• 期刊: JOURNAL OF CELLULAR BIOCHEMISTRY
• 影响因子: 4
• 作者: Zhou, Shuanhu

Age-related decline in osteoblastogenesis and 1α-hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone.

人间充质干细胞中成骨细胞生成和1α-羟化酶/CYP27B1与年龄相关的下降：甲状旁腺激素刺激。

• DOI: 10.1111/j.1474-9726.2011.00735.x
• 发表时间: 2011-12
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Geng S;Zhou S;Glowacki J
• 通讯作者: Glowacki J

Reduced osteoclastogenesis and RANKL expression in marrow from women taking alendronate.

• DOI: 10.1007/s00223-011-9473-5
• 发表时间: 2011-04
• 期刊: CALCIFIED TISSUE INTERNATIONAL
• 影响因子: 4.2
• 作者: Eslami, Behnam;Zhou, Shuanhu;Van Eekeren, Inge;LeBoff, Meryl S.;Glowacki, Julie
• 通讯作者: Glowacki, Julie