PPAR gamma-2 expression in marrow stroma during aging

衰老过程中骨髓基质中 PPAR gamma-2 的表达

基本信息

批准号：
6897232
负责人：
Beata Anna Lecka-Czernik
金额：
$ 21.9万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-06-01 至 2007-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (Verbatim from the Applicant): Decreased osteoblastogenesis in old age is accompanied by an increase in adipogenesis in the bone marrow of animals and humans. Since osteoblasts and adipocytes share a common mesenchymal progenitor, it is hypothesized that the osteopenia associated with aging is the result of changes in mesenchymal cell commitment and differentiation in the bone marrow. These changes result in an increase in adipogenesis at the expense of osteoblastogenesis. We demonstrated that marrow stroma derived from old animals consists of a larger number of cells that express PPARgamma2, an adipocyte specific transcription factor, than marrow stroma derived from young animals. In addition, we have shown that forced expression of PPARgamma2 in cells of osteoblastic lineage causes their terminal differentiation to adipocytes and simultaneously suppresses the osteoblastic phenotype through an inhibition of expression of osteoblast-specific transcription factor Osf2/Cbfal. Based on the above, we propose the hypothesis that increased expression of PPARgamma2 in mesenchymal progenitors, and/or production of PPARgamma2 ligands, causes increased marrow fat development and decreased osteoblast formation, resulting in the osteopenia that occurs with advancing age. To address aspects of this hypothesis, we propose the following Specific Aims: (1) determine the mechanisms responsible for suppression of PPARgamma2 promoter activity in cells of osteoblast lineage and bone marrow mesenchymal progenitors; (2) determine whether the anti-osteoblastic and/or pro-adipocytic effects of PPARgamma2 are mediated through SMADs; and (3) determine the role of PPARgamma2 on the fate of mesenchymal progenitors of bone marrow and bone formation in vivo. Understanding mechanisms which lead to increased adipogenesis and decreased osteoblastogenesis with aging may create the possibility for direct modulation of the fate of mesenchymal progenitor cells by preventing adipogenic conversion of potential osteoblasts. Such intervention may slow down or even prevent age-related bone loss.

描述（申请人的逐字化）：旧的成骨细胞生成减少年龄伴随着动物骨髓中的脂肪形成增加和人类。由于成骨细胞和脂肪细胞共享一个常见的间充质祖先，假设与衰老相关的骨质减少症是间充质细胞承诺和分化的变化的结果骨髓。这些变化导致成年以费用增加成骨细胞生成。我们证明了骨髓的基质来自旧动物由表达ppargamma2的大量细胞组成，一个脂肪细胞特异性转录因子，而不是源自幼小的骨髓基质动物。此外，我们已经表明了ppargamma2在成骨细胞谱系的细胞导致其末端分化脂肪细胞和同时抑制成骨细胞表型抑制成骨细胞特异性转录因子的表达 OSF2/CBFAL。基于上述，我们提出了增加的假设 ppargamma2在间充质祖细胞中的表达和/或产生 ppargamma2配体导致骨髓脂肪发育增加并减少成骨细胞的形成，导致骨质减少症随着前进而发生年龄。为了解决该假设的各个方面，我们提出以下特定目的：（1）确定负责抑制ppargamma2的机制成骨细胞谱系和骨髓间充质细胞中的启动子活性祖先；（2）确定抗肌细胞和/或促脂肪细胞是否是否 ppargamma2的作用是通过smads介导的。（3）确定骨髓和骨间充质祖细胞的命运上的ppargamma2 体内形成。了解导致增加的机制随着衰老的脂肪生成和成骨细胞生成的减少可能会造成直接调节间充质祖细胞命运的可能性通过防止潜在成骨细胞的成脂转化。这种干预可能会减慢甚至可以防止与年龄相关的骨质流失。