ROLE OF TGF-B INDUCIBLE EARLY GENE IN OSTEOCLASTOGENESIS

破骨细胞数量的调节对破骨细胞介导的骨降解有深远的影响， 病理性骨丢失和正常骨代谢期间。TGF-β 1在骨环境中丰富， 与破骨细胞分化的调节有关。我们发现了TIEG 1（TIEG）， 在TGF-受体处理后人成骨细胞中表达迅速增加的转录因子。 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。骸骨从 与年龄相比，这些小鼠更虚弱和更小， 匹配的野生型同窝仔。来自TIEG-/-小鼠的骨髓和脾脏来源的破骨细胞前体， 体外分化成破骨细胞的能力增强，NF κ B活化增强。此外，TGF-β 1 与野生型破骨细胞前体不同，在分化过程中的处理不刺激分化 小鼠颅骨来源的TIEG-/-成骨细胞支持破骨细胞分化的能力降低， 部分原因是OPG增加和RANKL表达减少。这些观察和发表的 文献导致我们中心假设TIEG在破骨细胞前体和成骨细胞中表达 支持细胞在调节破骨细胞分化和破骨细胞前体TIEG中是重要 表达对于TGF-β 1刺激分化是必需的。为了验证这一假设， 这个建议是为了1.阐明TIEG-/-中NF κ B途径活化增强的机制 破骨细胞前体2.解决增强的NF κ B信号传导在肿瘤细胞分化增加中的作用， TIEG-/-破骨细胞前体。3.确定TIEG在TGF-β 1刺激破骨细胞前体中的作用 体外分化。4.发现OPG表达增加的分子机制 体外培养的TIEG-/-颅骨细胞的mRNA和蛋白。5. TIEG刺激机制的探讨 RANKL基因在成骨细胞中的表达。由于骨丢失的速率主要取决于 破骨细胞，了解破骨细胞分化的调节可能会提供重要的途径， 在病理性骨丢失期间减缓骨降解的疗法。这些研究将增加这方面的知识 增加我们对破骨细胞介导的骨质流失的理解。此外，这些研究将提供关键 破骨细胞分化的分子机制的信息。

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.