1. Cell Biology
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Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo

  1. Eben G Estell  Is a corresponding author
  2. Phuong T Le
  3. Yosta Vegting
  4. Hyeonwoo Kim
  5. Christiane Wrann
  6. Mary L Bouxsein
  7. Kenichi Nagano
  8. Roland Baron
  9. Bruce M Spiegelman
  10. Clifford J Rosen  Is a corresponding author
  1. Maine Medical Center Research Institute, United States
  2. Dana Farber Cancer Institute, United States
  3. MGH/Harvard Medical School, United States
  4. Harvard Medical School, United States
  5. Harvard University, United States
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Cite this article as: eLife 2020;9:e58172 doi: 10.7554/eLife.58172

Abstract

The myokine irisin facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In the current study we investigated whether irisin also directly regulates osteoclasts. In vitro, irisin (2-10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; this increase was blocked by a neutralizing antibody to integrin αVβ5. Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating 'clastokines'. Forced expression of the irisin precursor Fndc5 in transgenic C57BL/6J mice resulted in low bone mass at three ages, and greater in vitro osteoclastogenesis from Fndc5-transgenic bone marrow progenitors. This work demonstrates that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption, supporting the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone.

Data availability

All data generated or analysed during this study are included in the manuscript figures and supplementary tables.

Article and author information

Author details

  1. Eben G Estell

    Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, United States
    For correspondence
    eestell@mmc.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8319-6886
  2. Phuong T Le

    Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    No competing interests declared.
  3. Yosta Vegting

    Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, United States
    Competing interests
    No competing interests declared.
  4. Hyeonwoo Kim

    Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  5. Christiane Wrann

    MGH/Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  6. Mary L Bouxsein

    Medicine, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  7. Kenichi Nagano

    School of Dental Medicine, Harvard University, Boston, United States
    Competing interests
    No competing interests declared.
  8. Roland Baron

    Medicine, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  9. Bruce M Spiegelman

    Dana Farber Cancer Institute, Boston, United States
    Competing interests
    No competing interests declared.
  10. Clifford J Rosen

    Center for Clinical & Translational Research, Maine Medical Center Research Institute, Scarborough, United States
    For correspondence
    rosenc@mmc.org
    Competing interests
    Clifford J Rosen, Senior editor, eLife.

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (F32AR077382)

  • Eben G Estell
  • Roland Baron
  • Bruce M Spiegelman
  • Clifford J Rosen

National Institute on Aging (U19AG060917)

  • Eben G Estell
  • Clifford J Rosen

National Institute of General Medical Sciences (U54GM115516-01A1)

  • Clifford J Rosen

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112374)

  • Clifford J Rosen

National Institute of General Medical Sciences (1P20GM121301)

  • Clifford J Rosen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All wild type primary cell progenitors for osteoclast cultures with exogenous irisin were obtained from tissue harvested from male and female C57BL6/J mice housed and treated under a protocol approved by the Maine Medical Center Research Institute IACUC (1914)

Reviewing Editor

  1. Gordana Vunjak-Novakovic, Columbia University, United States

Publication history

  1. Received: April 23, 2020
  2. Accepted: August 11, 2020
  3. Accepted Manuscript published: August 11, 2020 (version 1)
  4. Version of Record published: August 24, 2020 (version 2)

Copyright

© 2020, Estell 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.

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