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J Bone Miner Res. 2018 Nov;33(11):2035-2047. doi: 10.1002/jbmr.3533. Epub 2018 Jul 24.

NR4A1 Regulates Motility of Osteoclast Precursors and Serves as Target for the Modulation of Systemic Bone Turnover.

Author information

1
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
2
Nikolaus Fiebiger Center of Molecular Medicine, University of Erlangen-Nuremberg, Erlangen, Germany.
3
School of Medicine, University of Cardiff, Cardiff, Wales.
4
Department of Biophysics, University of Erlangen-Nuremberg, Erlangen, Germany.
5
Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.

Abstract

NR4A1 (Nur77 or NGFI-B), an orphan member of the nuclear receptor superfamily, has been identified as a key regulator of the differentiation and function of myeloid, lymphoid, and mesenchymal cells. The detailed role of NR4A1 in bone biology is incompletely understood. Here, we report a role for NR4A1 as novel factor controlling the migration and recruitment of osteoclast precursors during bone remodeling. Myeloid-specific but not osteoblast-specific deletion of NR4A1 resulted in osteopenia due to an increase in the number of bone-lining osteoclasts. Although NR4A1-deficient osteoclast precursors displayed a regular differentiation into mature osteoclasts, they showed a hyper-motile phenotype that was largely dependent on increased osteopontin expression, suggesting that expression of NR4A1 negatively controlled osteopontin-mediated recruitment of osteoclast precursors to the trabecular bone. Pharmacological activation of NR4A1, in turn, inhibited osteopontin expression and osteopontin-dependent migration of osteoclast precursors resulted in reduced abundance of bone-resorbing osteoclasts in vivo as well as in an ameliorated bone loss after ovariectomy in mice. This study identifies NR4A1 as a crucial player in the regulation of osteoclast biology and bone remodeling and highlights this nuclear receptor as a promising target for therapeutic intervention during the treatment of osteoporosis. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.

KEYWORDS:

CELL MIGRATION; NUCLEAR RECEPTORS; OSTEOCLASTS; OSTEOIMMUNOLOGY; OSTEOPOROSIS

PMID:
29949664
DOI:
10.1002/jbmr.3533
[Indexed for MEDLINE]
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