1. Cell Biology

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
https://doi.org/10.7554/eLife.58172
Share this article
Cite this article
  1. Eben G Estell
  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
(2020)
Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo
eLife 9:e58172.
https://doi.org/10.7554/eLife.58172
  2. Download BibTeX
  3. Download .RIS

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)

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.

Metrics

  • 2,643
    views
  • 464
    downloads
  • 84
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Eben G Estell
  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
(2020)
Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo
eLife 9:e58172.
https://doi.org/10.7554/eLife.58172

Share this article

https://doi.org/10.7554/eLife.58172

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Physics of Living Systems

    Catalytic growth in a shared enzyme pool ensures robust control of centrosome size

    Deb Sankar Banerjee, Shiladitya Banerjee
    Research Article

    Accurate regulation of centrosome size is essential for ensuring error-free cell division, and dysregulation of centrosome size has been linked to various pathologies, including developmental defects and cancer. While a universally accepted model for centrosome size regulation is lacking, prior theoretical and experimental works suggest a centrosome growth model involving autocatalytic assembly of the pericentriolar material. Here, we show that the autocatalytic assembly model fails to explain the attainment of equal centrosome sizes, which is crucial for error-free cell division. Incorporating latest experimental findings into the molecular mechanisms governing centrosome assembly, we introduce a new quantitative theory for centrosome growth involving catalytic assembly within a shared pool of enzymes. Our model successfully achieves robust size equality between maturing centrosome pairs, mirroring cooperative growth dynamics observed in experiments. To validate our theoretical predictions, we compare them with available experimental data and demonstrate the broad applicability of the catalytic growth model across different organisms, which exhibit distinct growth dynamics and size scaling characteristics.

    1. Cell Biology

    Mechanisms of PP2A-Ankle2 dependent nuclear reassembly after mitosis

    Jingjing Li, Xinyue Wang ... Vincent Archambault
    Research Article

    In animals, mitosis involves the breakdown of the nucleus. The reassembly of a nucleus after mitosis requires the reformation of the nuclear envelope around a single mass of chromosomes. This process requires Ankle2 (also known as LEM4 in humans) which interacts with PP2A and promotes the function of the Barrier-to-Autointegration Factor (BAF). Upon dephosphorylation, BAF dimers cross-bridge chromosomes and bind lamins and transmembrane proteins of the reassembling nuclear envelope. How Ankle2 functions in mitosis is incompletely understood. Using a combination of approaches in Drosophila, along with structural modeling, we provide several lines of evidence that suggest that Ankle2 is a regulatory subunit of PP2A, explaining how it promotes BAF dephosphorylation. In addition, we discovered that Ankle2 interacts with the endoplasmic reticulum protein Vap33, which is required for Ankle2 localization at the reassembling nuclear envelope during telophase. We identified the interaction sites of PP2A and Vap33 on Ankle2. Through genetic rescue experiments, we show that the Ankle2/PP2A interaction is essential for the function of Ankle2 in nuclear reassembly and that the Ankle2/Vap33 interaction also promotes this process. Our study sheds light on the molecular mechanisms of post-mitotic nuclear reassembly and suggests that the endoplasmic reticulum is not merely a source of membranes in the process, but also provides localized enzymatic activity.