Journal Article

DZNE-2021-00338

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Role of iRhoms 1 and 2 in Endochondral Ossification.

Fang, R. ; Haxaire, C. ; Otero, M. ; Lessard, S. ; Weskamp, G. ; McIlwain, D. R. ; Mak, T. W. ; Lichtenthaler, S. F.DZNE* ; Blobel, C. P. (Corresponding author)Extern*

2020
Molecular Diversity Preservation International Basel

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Please use a persistent id in citations: doi:10.3390/ijms21228732

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 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.

Keyword(s): ADAM17 Protein: genetics (MeSH) ; ADAM17 Protein: metabolism (MeSH) ; Animals (MeSH) ; Calcification, Physiologic: genetics (MeSH) ; Carrier Proteins: genetics (MeSH) ; Carrier Proteins: metabolism (MeSH) ; Cell Communication (MeSH) ; Cell Differentiation (MeSH) ; Cell Proliferation (MeSH) ; Chondrocytes: cytology (MeSH) ; Chondrocytes: metabolism (MeSH) ; Chondrogenesis: genetics (MeSH) ; Collagen Type II: genetics (MeSH) ; Collagen Type II: metabolism (MeSH) ; ErbB Receptors: genetics (MeSH) ; ErbB Receptors: metabolism (MeSH) ; Gene Expression Regulation (MeSH) ; Growth Plate: growth & development (MeSH) ; Growth Plate: metabolism (MeSH) ; Integrases: genetics (MeSH) ; Integrases: metabolism (MeSH) ; Membrane Proteins: deficiency (MeSH) ; Membrane Proteins: genetics (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Mice (MeSH) ; Mice, Knockout (MeSH) ; Osteogenesis: genetics (MeSH) ; Signal Transduction (MeSH) ; Transforming Growth Factor alpha: genetics (MeSH) ; Transforming Growth Factor alpha: metabolism (MeSH) ; ADAM17 ; a disintegrin and metalloprotease 17 ; endochondral ossification ; iRhom1, 2 ; inactive Rhomboid 1, 2 ; Carrier Proteins ; Col2a1 protein, mouse ; Collagen Type II ; Membrane Proteins ; Transforming Growth Factor alpha ; iRhom1 protein, mouse ; iRhom2 protein, mouse ; EGFR protein, mouse ; ErbB Receptors ; Cre recombinase ; Integrases ; ADAM17 Protein ; Adam17 protein, mouse

Note: Grant: Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s ExcellenceStrategy within the framework of the Munich Cluster for Systems Neurology EXC 2145 SyNergy—ID 390857198

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Contributing Institute(s):

1. Neuroproteomics (AG Lichtenthaler)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2020

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