1. <scp>A20</scp> controls <scp>RANK</scp> ‐dependent osteoclast formation and bone physiology
- Author
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Arne Martens, Pieter Hertens, Dario Priem, Vagelis Rinotas, Theodore Meletakos, Meropi Gennadi, Lisette Van Hove, Els Louagie, Julie Coudenys, Amélie De Muynck, Djoere Gaublomme, Mozes Sze, Jolanda van Hengel, Leen Catrysse, Esther Hoste, Jeffrey D Zajac, Rachel A Davey, Luc Van Hoorebeke, Tino Hochepied, Mathieu J M Bertrand, Marietta Armaka, Dirk Elewaut, and Geert van Loo
- Subjects
NF-kappa B ,Biology and Life Sciences ,osteoporosis ,bone ,Biochemistry ,Mice ,A20 ,inflammation ,osteoclast ,Medicine and Health Sciences ,Genetics ,Humans ,Animals ,Molecular Biology - Abstract
The anti-inflammatory protein A20 serves as a critical brake on NF-kappa B signaling and NF-kappa B-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-kappa B 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-kappa B signaling to control osteoclast differentiation, assuring proper bone development and turnover.
- Published
- 2022
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