Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
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DOI：
10.1371/journal.pone.0054853
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Sato K
中科院分区：
文献类型：
--
作者：
Saito K;Horiuchi K;Kimura T;Mizuno S;Yoda M;Morioka H;Akiyama H;Threadgill D;Okada Y;Toyama Y;Sato K
肿瘤坏死因子α转换酶(TACE)是一种膜结合蛋白水解酶，在肿瘤坏死因子α和表皮生长因子受体配体的功能调节中起重要作用。以前的研究已经证明了TACE在体内的关键作用，包括表皮发育、免疫反应和病理性新生血管生成等。然而，TACE对骨骼发育的潜在贡献仍不清楚。在本研究中，我们产生了一只TACE突变小鼠，在该突变小鼠中，在Col2a1启动子的控制下，Tace在软骨细胞中被有条件地破坏。这些突变的小鼠具有生育能力和生存能力，但与野生型动物相比，它们的长骨都短了约10%。组织学分析显示，TACE突变小鼠生长板中的肥大带较长，且TACE突变小鼠软骨-骨连接处的破骨细胞比其野生型小鼠的破骨细胞少。值得注意的是，我们发现在TACE缺陷的软骨中，骨保护素的转录增加，RANKL和MMP-13的转录减少，这表明这些基因的失调与TACE突变小鼠的骨骼缺陷有关。此外，我们还发现，在缺乏TACE的软骨组织中，EGFR的磷酸化水平显著降低，并且抑制EGFR信号转导增加了原代软骨细胞中护骨素的转录，减少了RANKL和MMP-13的转录。与此相一致的是，体内软骨细胞特异性去除EGFR导致的骨骼缺陷与在Tace突变小鼠中观察到的几乎相同。综上所述，这些数据表明，软骨细胞中的TACE-EGFR信号通过骨保护素、RANKL和基质金属蛋白酶-13的转录调控参与了生长板在出生后发育过程中的周转。
TNFα-converting enzyme (TACE) is a membrane-bound proteolytic enzyme with essential roles in the functional regulation of TNFα and epidermal growth factor receptor (EGFR) ligands. Previous studies have demonstrated critical roles for TACE in vivo, including epidermal development, immune response, and pathological neoangiogenesis, among others. However, the potential contribution of TACE to skeletal development is still unclear. In the present study, we generated a Tace mutant mouse in which Tace is conditionally disrupted in chondrocytes under the control of the Col2a1 promoter. These mutant mice were fertile and viable but all exhibited long bones that were approximately 10% shorter compared to those of wild-type animals. Histological analyses revealed that Tace mutant mice exhibited a longer hypertrophic zone in the growth plate, and there were fewer osteoclasts at the chondro-osseous junction in the Tace mutant mice than in their wild-type littermates. Of note, we found an increase in osteoprotegerin transcripts and a reduction in Rankl and Mmp-13 transcripts in the TACE-deficient cartilage, indicating that dysregulation of these genes is causally related to the skeletal defects in the Tace mutant mice. Furthermore, we also found that phosphorylation of EGFR was significantly reduced in the cartilage tissue lacking TACE, and that suppression of EGFR signaling increases osteoprotegerin transcripts and reduces Rankl and Mmp-13 transcripts in primary chondrocytes. In accordance, chondrocyte-specific abrogation of Egfr in vivo resulted in skeletal defects nearly identical to those observed in the Tace mutant mice. Taken together, these data suggest that TACE-EGFR signaling in chondrocytes is involved in the turnover of the growth plate during postnatal development via the transcriptional regulation of osteoprotegerin, Rankl, and Mmp-13.
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影响因子：
64.8
作者：
MIETTINEN, PJ;BERGER, JE;DERYNCK, R
通讯作者：
DERYNCK, R
影响因子：
4.4
作者：
Horiuchi, Keisuke;Kimura, Tokuhiro;Blobel, Carl P.
通讯作者：
Blobel, Carl P.
影响因子：
3.5
作者：
Sahin, Umut;Blobel, Carl P.
通讯作者：
Blobel, Carl P.
DOI：
10.1083/jcb.200310024
发表时间：
2004-06-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Nagano O;Murakami D;Hartmann D;De Strooper B;Saftig P;Iwatsubo T;Nakajima M;Shinohara M;Saya H
通讯作者：
Saya H
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I