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

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


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.


Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Remodeling*
  • Bone Resorption / pathology
  • Cancellous Bone / metabolism
  • Cell Count
  • Cell Differentiation
  • Cell Fusion
  • Cell Movement*
  • Gene Deletion
  • Homeostasis
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / deficiency
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Osteoblasts / metabolism
  • Osteoclasts / cytology*
  • Osteoclasts / metabolism*
  • Osteopontin / metabolism
  • Ovariectomy
  • Repressor Proteins / metabolism


  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Repressor Proteins
  • Osteopontin