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Title: | A20 controls RANK-dependent osteoclast formation and bone physiology. | Austin Authors: | Martens, Arne;Hertens, Pieter;Priem, Dario;Rinotas, Vagelis;Meletakos, Theodore;Gennadi, Meropi;Van Hove, Lisette;Louagie, Els;Coudenys, Julie;De Muynck, Amélie;Gaublomme, Djoere;Sze, Mozes;van Hengel, Jolanda;Catrysse, Leen;Hoste, Esther;Zajac, Jeffrey D ;Davey, Rachel A;Van Hoorebeke, Luc;Hochepied, Tino;Bertrand, Mathieu J M;Armaka, Marietta;Elewaut, Dirk;van Loo, Geert | Affiliation: | Center for Inflammation Research VIB, Ghent, Belgium. Medicine (University of Melbourne) Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece. Center for Inflammation Research VIB, Ghent, Belgium.. Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.. Department of Physics and Astronomy, Ghent University, Ghent, Belgium.. Center for Inflammation Research VIB, Ghent, Belgium.. Department of Rheumatology, Ghent University Hospital, Ghent, Belgium.. Center for Inflammation Research VIB, Ghent, Belgium.. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.. Department of Human Structure and Repair, Ghent University, Ghent, Belgium.. Center for Inflammation Research VIB, Ghent, Belgium.. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.. Department of Physics and Astronomy, Ghent University, Ghent, Belgium. Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece. |
Issue Date: | 4-Oct-2022 | Date: | 2022 | Publication information: | EMBO Reports 2022; 23(12) | Abstract: | The anti-inflammatory protein A20 serves as a critical brake on NF-κB signaling and NF-κB-dependent inflammation. In humans, polymorphisms in or near the TNFAIP3/A20 gene have been associated with several inflammatory disorders, including rheumatoid arthritis (RA), and experimental studies in mice have demonstrated that myeloid-specific A20 deficiency causes the development of a severe polyarthritis resembling human RA. Myeloid A20 deficiency also promotes osteoclastogenesis in mice, suggesting a role for A20 in the regulation of osteoclast differentiation and bone formation. We show here that osteoclast-specific A20 knockout mice develop severe osteoporosis, but not inflammatory arthritis. In vitro, osteoclast precursor cells from A20 deficient mice are hyper-responsive to RANKL-induced osteoclastogenesis. Mechanistically, we show that A20 is recruited to the RANK receptor complex within minutes of ligand binding, where it restrains NF-κB activation independently of its deubiquitinating activity but through its zinc finger (ZnF) 4 and 7 ubiquitin-binding functions. Together, these data demonstrate that A20 acts as a regulator of RANK-induced NF-κB signaling to control osteoclast differentiation, assuring proper bone development and turnover. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/31008 | DOI: | 10.15252/embr.202255233 | ORCID: | https://orcid.org/0000-0002-8994-5224 https://orcid.org/0000-0002-2390-3136 https://orcid.org/0000-0003-0645-0435 https://orcid.org/0000-0002-3181-431X https://orcid.org/0000-0001-9000-0626 https://orcid.org/0000-0003-0985-9076 https://orcid.org/0000-0002-7468-974X https://orcid.org/0000-0002-8427-4775 |
Journal: | EMBO Reports | PubMed URL: | 36194667 | Type: | Journal Article | Subjects: | A20 bone osteoclast - inflammation osteoporosis |
Appears in Collections: | Journal articles |
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