Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes.
Biphasic regulation of chondrocytes by Rela through induction of anti-apoptotic and catabolic target genes.
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通过诱导抗凋亡和分解代谢靶基因对软骨细胞的双相调节。
DOI：
10.1038/ncomms13336
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发表时间：
2016-11-10
影响因子：
16.6
通讯作者：
Saito, Taku
中科院分区：
文献类型：
--
作者：
Kobayashi, Hiroshi;Chang, Song Ho;Mori, Daisuke;Itoh, Shozo;Hirata, Makoto;Hosaka, Yoko;Taniguchi, Yuki;Okada, Keita;Mori, Yoshifumi;Yano, Fumiko;Chung, Ung-il;Akiyama, Haruhiko;Kawaguchi, Hiroshi;Tanaka, Sakae;Saito, Taku
体外研究表明，Rela/p65是介导NF-κB信号传导的关键亚基，参与软骨形成分化、细胞存活和分解代谢酶的产生。在这里，我们分析了Rela在胚胎肢体和成人关节软骨中的体内功能，发现Rela通过诱导包括Pik 3r 1在内的抗凋亡基因来保护软骨细胞免于凋亡。在骨骼发育过程中，Rela的纯合敲除通过增强软骨细胞凋亡导致生长受损，而Rela的杂合敲除不改变生长。在关节软骨中，7周时Rela的纯合敲除通过增强软骨细胞凋亡导致骨关节炎的显著加速，而Rela的杂合敲除通过抑制分解代谢基因表达导致骨关节炎发展的抑制。单倍不足或低剂量IKK抑制剂抑制分解代谢基因表达，但不改变抗凋亡基因表达。Rela对软骨细胞的双相调节有助于理解骨关节炎的病理生理学。 Rela是一种转录因子，在软骨的固定和固定中具有看似矛盾的作用。在这里，作者发现Rela可以防止软骨细胞凋亡，纯合基因敲除会导致成人骨关节炎加速，而杂合基因敲除通过维持野生型对凋亡的影响但抑制分解代谢基因表达来抑制骨关节炎。
In vitro studies have shown that Rela/p65, a key subunit mediating NF-κB signalling, is involved in chondrogenic differentiation, cell survival and catabolic enzyme production. Here, we analyse in vivo functions of Rela in embryonic limbs and adult articular cartilage, and find that Rela protects chondrocytes from apoptosis through induction of anti-apoptotic genes including Pik3r1. During skeletal development, homozygous knockout of Rela leads to impaired growth through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela does not alter growth. In articular cartilage, homozygous knockout of Rela at 7 weeks leads to marked acceleration of osteoarthritis through enhanced chondrocyte apoptosis, whereas heterozygous knockout of Rela results in suppression of osteoarthritis development through inhibition of catabolic gene expression. Haploinsufficiency or a low dose of an IKK inhibitor suppresses catabolic gene expression, but does not alter anti-apoptotic gene expression. The biphasic regulation of chondrocytes by Rela contributes to understanding the pathophysiology of osteoarthritis. Rela is a transcription factor shown to have seemingly contradictory roles in anabolism and catabolism of cartilage. Here the authors find that Rela prevents chondrocyte apoptosis and that homozygous knockout causes accelerated osteoarthritis in adults, whereas heterozygous knockout suppresses osteoarthritis by maintaining wild-type effects on apoptosis but inhibiting catabolic gene expression.
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影响因子：
10.5
作者：
Li, QT;Lu, QX;Verma, IM
通讯作者：
Verma, IM
骨关节炎的炎症。
影响因子：
5.1
作者：
Goldring MB;Otero M
通讯作者：
Otero M
影响因子：
7
作者：
Lopez-Armada, M. J.;Carames, B.;Blanco, F. J.
通讯作者：
Blanco, F. J.
影响因子：
64.8
作者：
Kanegae, Y;Tavares, AT;Verma, IM
通讯作者：
Verma, IM
影响因子：
2.7
作者：
Hilton, Matthew J.;Tu, Xiaolin;Long, Fanxin
通讯作者：
Long, Fanxin