ROLE OF TGF-B INDUCIBLE EARLY GENE IN OSTEOCLASTOGENESIS

TGF-B诱导早期基因在破骨细胞生成中的作用

• 批准号: 7577441
• 负责人: MERRY JO OURSLER
• 金额: $ 30.98万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577441
• 关键词: Age; Binding; Calvaria; Cell Culture Techniques; Cells; Data; Defect; Disease; Environment; Gene Expression; Genes; Goals; Head; Human; In Vitro; Knowledge; Laboratories; Lead; Literature; MADH7 gene; Marrow; Mediating; Messenger RNA; Molecular; Mus; NF-kappa B; NFKB Activation Pathway; Osteoblasts; Osteoclasts; Osteolysis; Osteoporosis; Pathology; Pathway interactions; Phosphorylation; Play; Proteins; Publishing; Regulation; Repression; Research Personnel; Role; Signal Transduction; Skeleton; Spleen; Supporting Cell; TNFSF11 gene; Testing; Work; bone; bone loss; bone metabolism; bone quality; c-fms Proto-Oncogenes; design; osteoclastogenesis; programs; promoter; response; transcription factor; tumor

Modulation of osteoclast numbers has a profound influence on osteoclast-mediated bone degradation in both pathological bone loss and during normal bone metabolism. TGF-li is abundant in the bone environment and has been implicated in regulation of osteoclast differentiation. We have discovered TIEG1 (TIEG), a transcription factor whose expression is rapidly increased in human osteoblasts following TGF-R treatment. To better understand TIEG's role(s) in bone metabolism, we have generated mice lacking TIEG. Bones from these mice are weaker and smaller with increased trabecular spacing in the femoral head compared to age matched wildtype littermates. Marrow- and spleen-derived osteoclast precursors from the TIEG-/- mice have an amplified ability to differentiate into osteoclasts in vitro and enhanced NFKB activation. Moreover, TGF-fl treatment during differentiation did not stimulate differentiation, unlike osteoclast precursors from wildtype mice. Calvarial-derived TIEG-/- osteoblasts have a reduced capactiy to support osteoclast differentiation, in part due to increased OPG and decreased RANKL expression. These observations and the published literature lead to our central hypothesis that TIEG expression in both osteoclast precursors and osteoblastic support cells is important in modulating osteoclast differentiation and that osteoclast precursor TIEG expression is essential for TGF-li stimulation of differentiation. To test this hypothesis, the Specific Aims of this proposal are to 1. Elucidate the mechanisms by which NFKB pathway activation is enhanced in TIEG-/- osteoclast precursors. 2. Resolve the role of enhanced NFKB signaling in the increased differentiation of TIEG-/- osteoclast precursors. 3. Determine the roles of TIEG in TGF-li stimulation of osteoclast precursor differentiation in vitro. 4. Discover the molecular mechanisms involved in the increased expression of OPG mRNA and protein in TIEG-/- calvarial cells cultured in vitro. 5. Ascertain the mechanism of TIEG stimulation of RANKL gene expression in osteoblasts. Since the rate of bone loss is mainly determined by the number of osteoclasts, understanding regulation of osteoclast differentiation is likely to provide important avenues for therapies to slow bone degradation during pathological bone loss. These studies will add to this knowledge and increase our understanding of osteoclast-mediated bone loss. Further, these studies should provide key information on the molecular mechanisms of osteoclast differentiation.

破骨细胞数的调节对两者的破骨细胞介导的骨降解都有深远的影响 病理骨质流失和正常骨代谢。 TGF-LI在骨环境中丰富 与破骨细胞分化有关。我们发现了tieg1（tieg），一个 TGF-R处理后，其表达在人骨细胞中的表达迅速增加。 为了更好地理解扎格在骨代谢中的作用，我们产生了缺乏绑扎的小鼠。骨头来自 与年龄相比 匹配的Wildtype窝窝。绑带 - / - 小鼠的骨髓和脾脏衍生的破骨细胞前体 在体外和增强的NFKB激活中分化为破骨细胞的扩增能力。而且，TGF-FL 与野生型的破骨细胞前体不同，分化过程中的治疗不会刺激分化 老鼠。在 部分是由于OPG增加和RANKL表达降低所致。这些观察和已发表的 文献导致了我们的中心假设，即在破骨细胞前体和成骨细胞中表达的表达 支持细胞对于调节破骨细胞分化和破骨细胞前体系列很重要 表达对于TGF-LI刺激分化至关重要。为了检验这一假设， 该提议为1。阐明了扎带中NFKB途径激活增强的机制 - / - 破骨细胞前体。 2。解决增强的NFKB信号在增加的分化中的作用 拉格 - / - 破骨细胞前体。 3。确定扎格在TGF-LI刺激破骨细胞前体中的作用 体外分化。 4。发现与OPG表达增加有关的分子机制 扎根 - / - 钙钙细胞中的mRNA和蛋白质在体外培养。 5。确定绑扎刺激的机制 在成骨细胞中的RANKL基因表达。由于骨质流失率主要取决于 破骨细胞，了解破骨细胞分化的调节可能会为 在病理骨质流失期间减慢骨骼降解的疗法。这些研究将增加这一知识 并增加我们对破骨细胞介导的骨质流失的理解。此外，这些研究应提供关键 有关破骨细胞分化的分子机制的信息。