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 E. und Blobel, Carl P. (2020): Role of iRhoms 1 and 2 in Endochondral Ossification. In: International Journal of Molecular Sciences, Bd. 21, Nr. 22, 8732

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 alpha 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 increment Ch). The resulting iR2-/-iR1 increment 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 increment Ch chondrocytes had strongly reduced shedding of TGF alpha and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2-/-iR1 increment Ch mice closely resembled the abnormal growth plate in A17 increment Ch mice and was similar to growth plates in Tgf alpha-/- mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGF alpha/EGFR signaling axis during endochondral ossification.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198