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Role of iRhoms 1 and 2 in Endochondral Ossification

Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal develo...

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Autores principales: Fang, Renpeng, Haxaire, Coline, Otero, Miguel, Lessard, Samantha, Weskamp, Gisela, McIlwain, David R., Mak, Tak W., Lichtenthaler, Stefan F., Blobel, Carl P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699240/
https://www.ncbi.nlm.nih.gov/pubmed/33227998
http://dx.doi.org/10.3390/ijms21228732
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author Fang, Renpeng
Haxaire, Coline
Otero, Miguel
Lessard, Samantha
Weskamp, Gisela
McIlwain, David R.
Mak, Tak W.
Lichtenthaler, Stefan F.
Blobel, Carl P.
author_facet Fang, Renpeng
Haxaire, Coline
Otero, Miguel
Lessard, Samantha
Weskamp, Gisela
McIlwain, David R.
Mak, Tak W.
Lichtenthaler, Stefan F.
Blobel, Carl P.
author_sort Fang, Renpeng
collection PubMed
description Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification.
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spelling pubmed-76992402020-11-29 Role of iRhoms 1 and 2 in Endochondral Ossification Fang, Renpeng Haxaire, Coline Otero, Miguel Lessard, Samantha Weskamp, Gisela McIlwain, David R. Mak, Tak W. Lichtenthaler, Stefan F. Blobel, Carl P. Int J Mol Sci Article Growth of the axial and appendicular skeleton depends on endochondral ossification, which is controlled by tightly regulated cell–cell interactions in the developing growth plates. Previous studies have uncovered an important role of a disintegrin and metalloprotease 17 (ADAM17) in the normal development of the mineralized zone of hypertrophic chondrocytes during endochondral ossification. ADAM17 regulates EGF-receptor signaling by cleaving EGFR-ligands such as TGFα from their membrane-anchored precursor. The activity of ADAM17 is controlled by two regulatory binding partners, the inactive Rhomboids 1 and 2 (iRhom1, 2), raising questions about their role in endochondral ossification. To address this question, we generated mice lacking iRhom2 (iR2−/−) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (iR1∆Ch). The resulting iR2−/−iR1∆Ch mice had retarded bone growth compared to iR2−/− mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary iR2−/−iR1∆Ch chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2−/−iR1∆Ch mice closely resembled the abnormal growth plate in A17∆Ch mice and was similar to growth plates in Tgfα−/− mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFα/EGFR signaling axis during endochondral ossification. MDPI 2020-11-19 /pmc/articles/PMC7699240/ /pubmed/33227998 http://dx.doi.org/10.3390/ijms21228732 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fang, Renpeng
Haxaire, Coline
Otero, Miguel
Lessard, Samantha
Weskamp, Gisela
McIlwain, David R.
Mak, Tak W.
Lichtenthaler, Stefan F.
Blobel, Carl P.
Role of iRhoms 1 and 2 in Endochondral Ossification
title Role of iRhoms 1 and 2 in Endochondral Ossification
title_full Role of iRhoms 1 and 2 in Endochondral Ossification
title_fullStr Role of iRhoms 1 and 2 in Endochondral Ossification
title_full_unstemmed Role of iRhoms 1 and 2 in Endochondral Ossification
title_short Role of iRhoms 1 and 2 in Endochondral Ossification
title_sort role of irhoms 1 and 2 in endochondral ossification
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699240/
https://www.ncbi.nlm.nih.gov/pubmed/33227998
http://dx.doi.org/10.3390/ijms21228732
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