Dataset Information

Role of iRhoms 1 and 2 in Endochondral Ossification.

ABSTRACT: 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 TGF? 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 TGF? 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 Tgf?-/- mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGF?/EGFR signaling axis during endochondral ossification.

SUBMITTER: Fang R

PROVIDER: S-EPMC7699240 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Role of iRhoms 1 and 2 in Endochondral Ossification.

Fang Renpeng R Haxaire Coline C Otero Miguel M Lessard Samantha S Weskamp Gisela G McIlwain David R DR Mak Tak W TW Lichtenthaler Stefan F SF Blobel Carl P CP

International journal of molecular sciences 20201119 22

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 ...[more]

PMID: 33227998

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Role of iRhoms 1 and 2 in Endochondral Ossification.

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Role of iRhoms 1 and 2 in Endochondral Ossification.

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