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.

破骨细胞数量的调节对破骨细胞介导的骨降解具有深远的影响 病理性骨质流失和正常骨代谢期间。 TGF-li 在骨环境中含量丰富，并且 与破骨细胞分化的调节有关。我们发现了 TIEG1 (TIEG)， TGF-R 处理后，其表达在人成骨细胞中迅速增加的转录因子。 为了更好地了解 TIEG 在骨代谢中的作用，我们培育了缺乏 TIEG 的小鼠。骨头来自 与年龄相比，这些小鼠更虚弱、更小，股骨头小梁间距增加 匹配的野生型同窝仔。来自 TIEG-/- 小鼠的骨髓和脾源性破骨细胞前体具有 增强体外分化为破骨细胞的能力并增强 NFKB 激活。此外，TGF-fl 与野生型的破骨细胞前体不同，分化期间的治疗不会刺激分化 老鼠。颅骨来源的 TIEG-/- 成骨细胞支持破骨细胞分化的能力降低， 部分归因于 OPG 增加和 RANKL 表达减少。这些观察结果和已发表的 文献引出了我们的中心假设，即 TIEG 在破骨细胞前体和成骨细胞中表达 支持细胞对于调节破骨细胞分化很重要，破骨细胞前体 TIEG 表达对于TGF-β1刺激分化是必需的。为了检验这一假设，具体目标 该提案旨在 1. 阐明 TIEG-/- 中增强 NFKB 通路激活的机制 破骨细胞前体。 2.解决NFKB信号增强在增加分化中的作用 TIEG-/- 破骨细胞前体。 3.确定TIEG在破骨细胞前体的TGF-li刺激中的作用 体外分化。 4. 发现OPG表达增加的分子机制 体外培养的 TIEG-/- 颅骨细胞中的 mRNA 和蛋白质。 5. 确定 TIEG 刺激的机制 成骨细胞中 RANKL 基因表达的影响。由于骨丢失的速度主要由骨量决定。 破骨细胞，了解破骨细胞分化的调节可能为破骨细胞分化提供重要途径 病理性骨质流失期间减缓骨质退化的疗法。这些研究将丰富这方面的知识 并增加我们对破骨细胞介导的骨质流失的了解。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。