| First Author | Fang R | Year | 2020 |
| Journal | Int J Mol Sci | Volume | 21 |
| Issue | 22 | PubMed ID | 33227998 |
| Mgi Jnum | J:303061 | Mgi Id | MGI:6511616 |
| Doi | 10.3390/ijms21228732 | Citation | Fang R, et al. (2020) Role of iRhoms 1 and 2 in Endochondral Ossification. Int J Mol Sci 21(22):8732 |
| abstractText | 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 TGFalpha 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 (iR1Ch). The resulting iR2-/-iR1Ch 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-/-iR1Ch chondrocytes had strongly reduced shedding of TGFalpha and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in iR2-/-iR1Ch mice closely resembled the abnormal growth plate in A17Ch mice and was similar to growth plates in Tgfalpha-/- mice or mice with EGFR mutations. These data support a model in which iRhom1 and 2 regulate bone growth by controlling the ADAM17/TGFalpha/EGFR signaling axis during endochondral ossification. |
