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

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.

The emerging role of IMD 0354 on bone homeostasis by suppressing osteoclastogenesis and bone resorption, but without affecting bone formation

“…Osteoporosis is known as the most common metabolic bone disease and is caused by an imbalance between bone formation and bone resorption 1 , placing a substantial public health burden on the aging population 2,3 . This disorder is characterized by disturbance of the bone microarchitecture leading to diminished bone stability and enhanced risk of fractures 4 .…”

Frontline Science: Characterization and regulation of osteoclast precursors following chronic Porphyromonas gingivalis infection

“…However, a unique gene profile was identified in CD11b + c‐fms + Ly6C hi population after Pg infection. Genes reported as positive regulators of OC differentiation, such as S100A8, S100A9, and Foxm1, 41,45,46 were significantly up‐regulated in CD11b + c‐fms + Ly6C hi population of Pg‐ infected mice, whereas genes known as negative regulators of OC differentiation, like Irf8, Mafb, NR4A1, and ApoE, 40,44,51,52 were significantly down‐regulated in these cells. This outcome may account for the increased osteoclastogenic potential of these cells following Pg infection.…”

“…Relative expression of OC‐related genes was normalized to β‐actin gene. Primers used are listed in Supplementary Table 1 39‐41 …”

Updates on Osteoimmunology: What's New on the Cross-Talk Between Bone and Immune System

“…Moreover, Scholtysek and colleagues clarified a role for NR4A1 in controlling pre-osteoclast recruitment and migration, with an effect linked to the myeloid lineage. In fact, myeloid-specific but not osteoblast-specific deletion of NR4A1 resulted in osteopenia due to an increase of osteoclast number (48). The immune-related factors influencing osteoclast formation and biology are many more; a list of the most important ones is presented in Table 2.…”