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: 7207983
• 负责人: MERRY JO OURSLER
• 金额: $ 31.62万
• 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/7207983
• 关键词: Age; Binding; Calvaria; Cells; Cultured 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; Numbers; Osteoblasts; Osteoclasts; Osteolysis; Osteoporosis; Pathology, Other; Pathway interactions; Phosphorylation; Play; Proteins; Publishing; Rate; 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

DESCRIPTION (provided by applicant): Modulation of osteoclast numbers has a profound influence on osteoclast-mediated bone degradation in both pathological bone loss and during normal bone metabolism. TGF-( 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-( 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-( 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-( 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-( 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.

描述（由申请方提供）：在病理性骨丢失和正常骨代谢期间，破骨细胞数量的调节对破骨细胞介导的骨降解具有深远影响。TGF-β在骨环境中丰富，并与破骨细胞分化的调节有关。我们已经发现TIEG 1（TIEG），一种转录因子，其表达在TGF-β处理后在人成骨细胞中迅速增加。为了更好地理解TIEG在骨代谢中的作用，我们产生了缺乏TIEG的小鼠。与年龄匹配的野生型同窝小鼠相比，这些小鼠的骨更弱且更小，股骨头中的骨小梁间距增加。来自TIEG-/-小鼠的骨髓和脾脏来源的破骨细胞前体具有扩增的体外分化成破骨细胞的能力和增强的NFkB活化。此外，与野生型小鼠的破骨细胞前体不同，在分化期间TGF-β处理不刺激分化。颅骨来源的TIEG-/-成骨细胞支持破骨细胞分化的能力降低，部分原因是OPG增加和RANKL表达降低。这些观察结果和已发表的文献导致我们的中心假设，即破骨细胞前体和成骨细胞支持细胞中的TIEG表达在调节破骨细胞分化中是重要的，破骨细胞前体TIEG表达对于TGF-β刺激分化是必需的。为了验证这一假设，本提案的具体目标是1.阐明TIEG-/-破骨细胞前体中NFkB途径活化增强的机制。2.解决增强的NFkB信号传导在TIEG-/-破骨细胞前体分化增加中的作用。3.确定TIEG在体外TGF-β刺激破骨细胞前体分化中的作用。4.探讨体外培养TIEG-/-颅骨细胞OPG mRNA和蛋白表达增加的分子机制。5.探讨TIEG刺激成骨细胞RANKL基因表达的机制。由于骨丢失的速率主要由破骨细胞的数量决定，因此了解破骨细胞分化的调节可能为减缓病理性骨丢失期间骨降解的治疗提供重要途径。这些研究将增加这方面的知识，并增加我们对破骨细胞介导的骨丢失的理解。此外，这些研究应提供破骨细胞分化的分子机制的关键信息。