High-mobility group box proteins modulate tumor necrosis factor-alpha expression in osteoclastogenesis via a novel deoxyribonucleic acid sequence.
High-mobility group box proteins modulate tumor necrosis factor-alpha expression in osteoclastogenesis via a novel deoxyribonucleic acid sequence.
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DOI：
10.1210/me.2007-0460
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发表时间：
2008-05
影响因子：
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通讯作者：
K. Yamoah;Alina Brebene;R. Baliram;K. Inagaki;G. Dolios;A. Arabi;Rinosha Majeed;H. Amano;Rong Wang;R. Yanagisawa;E. Abe
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文献类型：
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作者：
K. Yamoah;Alina Brebene;R. Baliram;K. Inagaki;G. Dolios;A. Arabi;Rinosha Majeed;H. Amano;Rong Wang;R. Yanagisawa;E. Abe
我们以前已经表明，缺乏TSH受体（TSHR）的小鼠表现出骨质疏松症，由于破骨细胞形成增加。在TSHR和TNF α双缺失小鼠中没有观察到这种增强的事实表明，可能涉及破骨细胞祖细胞（巨噬细胞）中TNF α的过度表达。目前尚不清楚TNF α表达在破骨细胞生成中是如何调节的。在这里，我们描述了一个核因子-κ B配体（RANKL）反应序列（CCG阿加CAG AGG TGT AGG GCC）的受体激活剂，其跨越TNF α基因5 '侧翼区的-157至-137 bp，作为顺式作用调节元件发挥作用。我们进一步展示了RANKL处理如何刺激高迁移率族蛋白（HMGB）HMGB 1和HMGB 2结合RANKL响应序列并上调TNF α转录。外源性HMGB促进细胞因子（包括TNF α）的表达以及破骨细胞的形成。相反，TSH抑制HMGB和TNF α的表达以及破骨细胞的形成。这些结果表明HMGB在破骨细胞生成中起关键作用。我们还发现，在TSHR缺失小鼠和TNF α缺失小鼠中，HMGB和TNF α的表达与破骨细胞形成之间存在直接相关性。综上所述，我们得出结论，HMGB和TNF α在破骨细胞生成和骨重建的调节中起着关键作用。
We have previously shown that mice lacking the TSH receptor (TSHR) exhibit osteoporosis due to enhanced osteoclast formation. The fact that this enhancement is not observed in double-null mice of TSHR and TNFalpha suggests that TNFalpha overexpression in osteoclast progenitors (macrophages) may be involved. It is unknown how TNFalpha expression is regulated in osteoclastogenesis. Here, we describe a receptor activator for nuclear factor-kappaB ligand (RANKL)-responsive sequence (CCG AGA CAG AGG TGT AGG GCC), spanning from -157 to -137 bp of the 5'-flanking region of the TNFalpha gene, which functions as a cis-acting regulatory element. We further show how RANKL treatment stimulates the high-mobility group box proteins (HMGB) HMGB1 and HMGB2 to bind the RANKL-responsive sequence and up-regulates TNFalpha transcription. Exogenous HMGB elicits the expression of cytokines, including TNFalpha, as well as osteoclast formation. Conversely, TSH inhibits the expression of HMGB and TNFalpha and the formation of osteoclasts. These results suggest that HMGB play a pivotal role in osteoclastogenesis. We also show a direct correlation between the expression of HMGB and TNFalpha and osteoclast formation in TSHR-null mice and TNFalpha-null mice. Taken together, we conclude that HMGB and TNFalpha play critical roles in the regulation of osteoclastogenesis and the remodeling of bone.