1. Cell Biology
  2. Human Biology and Medicine
Download icon

Nur77 prevents excessive osteoclastogenesis by inducing ubiquitin ligase Cbl-b to mediate NFATc1 self-limitation

  1. Xiaoxiao Li
  2. Wei Wei
  3. HoangDinh Huynh
  4. Hao Zuo
  5. Xueqian Wang
  6. Yihong Wan  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
Research Article
  • Cited 10
  • Views 1,422
  • Annotations
Cite this article as: eLife 2015;4:e07217 doi: 10.7554/eLife.07217

Abstract

Osteoclasts are bone-resorbing cells essential for skeletal remodeling. However, over-active osteoclasts can cause bone degenerative disorders. Therefore, the level of NFATc1, the master transcription factor of osteoclast, must be tightly controlled. Although the activation and amplification of NFATc1 have been extensively studied, how NFATc1 signaling is eventually resolved is unclear. Here, we uncover a novel and critical role of the orphan nuclear receptor Nur77 in mediating an NFATc1 self-limiting regulatory loop to prevent excessive osteoclastogenesis. Nur77 deletion leads to low bone mass owing to augmented osteoclast differentiation and bone resorption. Mechanistically, NFATc1 induces Nur77 expression at late stage of osteoclast differentiation; in turn, Nur77 transcriptionally up-regulates E3 ubiquitin ligase Cbl-b, which triggers NFATc1 protein degradation. These findings not only identify Nur77 as a key player in osteoprotection and a new therapeutic target for bone diseases, but also elucidate a previously unrecognized NFATc1→Nur77→Cblb⎯•NFATc1 feedback mechanism that confers NFATc1 signaling autoresolution.

Article and author information

Author details

  1. Xiaoxiao Li

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei Wei

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. HoangDinh Huynh

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Hao Zuo

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xueqian Wang

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yihong Wan

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    yihong.wan@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All protocols for mouse experiments were approved under number 2008-0324 by the Institutional Animal Care and Use Committee of UTSW.

Reviewing Editor

  1. Janet Rossant, University of Toronto, Canada

Publication history

  1. Received: February 26, 2015
  2. Accepted: July 13, 2015
  3. Accepted Manuscript published: July 14, 2015 (version 1)
  4. Version of Record published: July 29, 2015 (version 2)

Copyright

© 2015, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,422
    Page views
  • 343
    Downloads
  • 10
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)