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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MDPI AG
2020-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/22/8732 |
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| author | Renpeng Fang Coline Haxaire Miguel Otero Samantha Lessard Gisela Weskamp David R. McIlwain Tak W. Mak Stefan F. Lichtenthaler Carl P. Blobel |
| author_facet | Renpeng Fang Coline Haxaire Miguel Otero Samantha Lessard Gisela Weskamp David R. McIlwain Tak W. Mak Stefan F. Lichtenthaler Carl P. Blobel |
| author_sort | Renpeng Fang |
| collection | DOAJ |
| 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 (<i>iR2−/−</i>) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (<i>iR1∆Ch</i>). The resulting <i>iR2−/−iR1∆Ch</i> mice had retarded bone growth compared to <i>iR2−/−</i> mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary <i>iR2−/−iR1∆Ch</i> chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in <i>iR2−/−iR1∆Ch</i> mice closely resembled the abnormal growth plate in <i>A17∆Ch</i> mice and was similar to growth plates in <i>Tgfα−/−</i> 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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| id | doaj.art-c94720f1cc3c4ef5883b4df715efa56d |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T14:45:10Z |
| publishDate | 2020-11-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c94720f1cc3c4ef5883b4df715efa56d2023-11-20T21:30:20ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-012122873210.3390/ijms21228732Role of iRhoms 1 and 2 in Endochondral OssificationRenpeng Fang0Coline Haxaire1Miguel Otero2Samantha Lessard3Gisela Weskamp4David R. McIlwain5Tak W. Mak6Stefan F. Lichtenthaler7Carl P. Blobel8Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha 410008, ChinaArthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USAOrthopedic Soft Tissue Research Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USAOrthopedic Soft Tissue Research Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USAArthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USABaxter Laboratory in Stem Cell Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USACampbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, CanadaGerman Center for Neurodegenerative Diseases (DZNE), 81377 Munich, GermanyArthritis and Tissue Degeneration Program, Hospital for Special Surgery at Weill Cornell Medicine, New York, NY 10021, USAGrowth 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 (<i>iR2−/−</i>) with floxed alleles of iRhom1 that were specifically deleted in chondrocytes by Col2a1-Cre (<i>iR1∆Ch</i>). The resulting <i>iR2−/−iR1∆Ch</i> mice had retarded bone growth compared to <i>iR2−/−</i> mice, caused by a significantly expanded zone of hypertrophic mineralizing chondrocytes in the growth plate. Primary <i>iR2−/−iR1∆Ch</i> chondrocytes had strongly reduced shedding of TGFα and other ADAM17-dependent EGFR-ligands. The enlarged zone of mineralized hypertrophic chondrocytes in <i>iR2−/−iR1∆Ch</i> mice closely resembled the abnormal growth plate in <i>A17∆Ch</i> mice and was similar to growth plates in <i>Tgfα−/−</i> 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.https://www.mdpi.com/1422-0067/21/22/8732a disintegrin and metalloprotease 17ADAM17inactive Rhomboid 1, 2iRhom1, 2endochondral ossification |
| spellingShingle | Renpeng Fang Coline Haxaire Miguel Otero Samantha Lessard Gisela Weskamp David R. McIlwain Tak W. Mak Stefan F. Lichtenthaler Carl P. Blobel Role of iRhoms 1 and 2 in Endochondral Ossification International Journal of Molecular Sciences a disintegrin and metalloprotease 17 ADAM17 inactive Rhomboid 1, 2 iRhom1, 2 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 | a disintegrin and metalloprotease 17 ADAM17 inactive Rhomboid 1, 2 iRhom1, 2 endochondral ossification |
| url | https://www.mdpi.com/1422-0067/21/22/8732 |
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