Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.

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, an...

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Main Authors: Kenta Saito, Keisuke Horiuchi, Tokuhiro Kimura, Sakiko Mizuno, Masaki Yoda, Hideo Morioka, Haruhiko Akiyama, David Threadgill, Yasunori Okada, Yoshiaki Toyama, Kazuki Sato
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2013-01-01
Series:PLoS ONE
Online Access:http://europepmc.org/articles/PMC3548805?pdf=render
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spelling doaj-157398e933014c438e68b19babe1973d2020-11-24T20:50:40ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0181e5485310.1371/journal.pone.0054853Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.Kenta SaitoKeisuke HoriuchiTokuhiro KimuraSakiko MizunoMasaki YodaHideo MoriokaHaruhiko AkiyamaDavid ThreadgillYasunori OkadaYoshiaki ToyamaKazuki SatoTNFα-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.http://europepmc.org/articles/PMC3548805?pdf=render
collection DOAJ
language English
format Article
sources DOAJ
author Kenta Saito
Keisuke Horiuchi
Tokuhiro Kimura
Sakiko Mizuno
Masaki Yoda
Hideo Morioka
Haruhiko Akiyama
David Threadgill
Yasunori Okada
Yoshiaki Toyama
Kazuki Sato
spellingShingle Kenta Saito
Keisuke Horiuchi
Tokuhiro Kimura
Sakiko Mizuno
Masaki Yoda
Hideo Morioka
Haruhiko Akiyama
David Threadgill
Yasunori Okada
Yoshiaki Toyama
Kazuki Sato
Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
PLoS ONE
author_facet Kenta Saito
Keisuke Horiuchi
Tokuhiro Kimura
Sakiko Mizuno
Masaki Yoda
Hideo Morioka
Haruhiko Akiyama
David Threadgill
Yasunori Okada
Yoshiaki Toyama
Kazuki Sato
author_sort Kenta Saito
title Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
title_short Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
title_full Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
title_fullStr Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
title_full_unstemmed Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
title_sort conditional inactivation of tnfα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2013-01-01
description 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.
url http://europepmc.org/articles/PMC3548805?pdf=render
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