A novel role for GADD45β as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation
A novel role for GADD45β as a mediator of MMP-13 gene expression during chondrocyte terminal differentiation
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DOI：
10.1074/jbc.m504202200
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发表时间：
2005-11-18
影响因子：
4.8
通讯作者：
Goldring, MB
中科院分区：
文献类型：
--
作者：
Ijiri, K;Zerbini, LF;Goldring, MB
生长停滞和DNA损伤诱导的45 β（GADD 45 β）基因产物与应激反应、细胞周期停滞和细胞凋亡有关。在这里，我们证明了GADD 45 β在胚胎生长板中的意外表达，并揭示了其作为终末软骨细胞分化过程中基质金属蛋白酶-13（MMP-13）表达的重要介质的新作用。我们确定GADD 45 β是骨形态发生蛋白-2（BMP-2）通过Smad 1/Runx 2依赖性途径诱导的一个突出的早期反应基因。由于该途径参与骨骼发育，我们检查了小鼠胚胎生长板，并观察到肥大前软骨细胞中Gadd 45 β mRNA的表达与Runx 2蛋白一致，而GADD 45 β蛋白主要定位于晚期肥大软骨细胞的细胞核中，其中Mmp-13 mRNA表达。在Gadd 45 β（-/-）小鼠胚胎中，矿化缺陷和骨生长减少伴随着肥大区Mmp-13和Col 10a 1基因表达缺陷。体外转染小干扰RNA-GADD 45 β可阻断骺软骨细胞的终末分化及相关的Mmp-13和Col 10a 1 mRNA的表达。最后，GADD 45 β通过JNK介导的JunD磷酸化与Fra 2协同作用，与Runx 2协同作用，刺激软骨细胞中MMP-13启动子活性。这些观察结果表明，GADD 45 β在软骨细胞终末分化过程中起着重要作用。
The growth arrest and DNA damage-inducible 45 beta(GADD45 beta) gene product has been implicated in the stress response, cell cycle arrest, and apoptosis. Here we demonstrated the unexpected expression of GADD45 beta in the embryonic growth plate and uncovered its novel role as an essential mediator of matrix metalloproteinase-13 (MMP-13) expression during terminal chondrocyte differentiation. We identified GADD45 beta as a prominent early response gene induced by bone morphogenetic protein-2 (BMP-2) through a Smad1/Runx2-dependent pathway. Because this pathway is involved in skeletal development, we examined mouse embryonic growth plates, and we observed expression of Gadd45 beta mRNA coincident with Runx2 protein in pre-hypertrophic chondrocytes, whereas GADD45 beta protein was localized prominently in the nucleus in late stage hypertrophic chondrocytes where Mmp-13 mRNA was expressed. In Gadd45 beta(-/-) mouse embryos, defective mineralization and decreased bone growth accompanied deficient Mmp-13 and Col10a1 gene expression in the hypertrophic zone. Transduction of small interfering RNA-GADD45 beta in epiphyseal chondrocytes in vitro blocked terminal differentiation and the associated expression of Mmp-13 and Col10a1 mRNA in vitro. Finally, GADD45 beta stimulated MMP-13 promoter activity in chondrocytes through the JNK-mediated phosphorylation of JunD, partnered with Fra2, in synergy with Runx2. These observations indicated that GADD45 beta plays an essential role during chondrocyte terminal differentiation.