1. Stem Cells and Regenerative Medicine

Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass

  1. Bo Shen
  2. Kristy Vardy
  3. Payton Hughes
  4. Alpaslan Tasdogan
  5. Zhiyu Zhao
  6. Rui Yue
  7. Genevieve Crane
  8. Sean J Morrison  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. Tongji University, China
  3. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.42274
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Cite this article
  1. Bo Shen
  2. Kristy Vardy
  3. Payton Hughes
  4. Alpaslan Tasdogan
  5. Zhiyu Zhao
  6. Rui Yue
  7. Genevieve Crane
  8. Sean J Morrison
(2019)
Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass
eLife 8:e42274.
https://doi.org/10.7554/eLife.42274
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Abstract

We previously discovered a new osteogenic growth factor that is required to maintain adult skeletal bone mass, Osteolectin/Clec11a. Osteolectin acts on Leptin Receptor+ (LepR+) skeletal stem cells and other osteogenic progenitors in bone marrow to promote their differentiation into osteoblasts. Here we identity a receptor for Osteolectin, integrin a11, which is expressed by LepR+ cells and osteoblasts. a11b1 integrin binds Osteolectin with nanomolar affinity and is required for the osteogenic response to Osteolectin. Deletion of Itga11 (which encodes a11) from mouse and human bone marrow stromal cells impaired osteogenic differentiation and blocked their response to Osteolectin. Like Osteolectin deficient mice, Lepr-cre; Itga11fl/fl mice appeared grossly normal but exhibited reduced osteogenesis and accelerated bone loss during adulthood. Osteolectin binding to a11b1 promoted Wnt pathway activation, which was necessary for the osteogenic response to Osteolectin. This reveals a new mechanism for maintenance of adult bone mass: Wnt pathway activation by Osteolectin/a11b1 signaling.

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Author details

  1. Bo Shen

    Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5237-6144

  2. Kristy Vardy

    Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.

  3. Payton Hughes

    Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.

  4. Alpaslan Tasdogan

    Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.

  5. Zhiyu Zhao

    Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6308-6997

  6. Rui Yue

    Institute of Regenerative Medicine, Tongji University, Shanghai, China
    Competing interests
    Rui Yue, Was an inventor on a pending patent application claiming the use of Osteolectin to promote bone formation. The patent application has not been licensed, so has no existing financial interest in it. WO patent application number: WO2016172026A1.

  7. Genevieve Crane

    Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9274-0214

  8. Sean J Morrison

    Children's Medical Center Research Institute at UT Southwestern, Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    sean.morrison@utsouthwestern.edu
    Competing interests
    Sean J Morrison, Is an inventor on a pending patent application claiming the use of Osteolectin to promote bone formation. The IP has not been licensed, so there is no existing financial interest. WO patent application number: WO2016172026A1. Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1587-8329

Funding

Howard Hughes Medical Institute

  • Sean J Morrison

National Institutes of Health (AG02494514)

  • Sean J Morrison

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

Ethics

Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All procedures were approved by the UT Southwestern Institutional Animal Care and Use Committee (protocol number 2016-101334-G).

Reviewing Editor

  1. Clifford J Rosen, Maine Medical Center Research Institute, United States

Version history

  1. Received: September 24, 2018
  2. Accepted: January 5, 2019
  3. Accepted Manuscript published: January 11, 2019 (version 1)
  4. Version of Record published: January 28, 2019 (version 2)
  5. Version of Record updated: January 30, 2019 (version 3)

Copyright

© 2019, Shen 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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  1. Bo Shen
  2. Kristy Vardy
  3. Payton Hughes
  4. Alpaslan Tasdogan
  5. Zhiyu Zhao
  6. Rui Yue
  7. Genevieve Crane
  8. Sean J Morrison
(2019)
Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass
eLife 8:e42274.
https://doi.org/10.7554/eLife.42274

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Further reading

    1. Developmental Biology

    Clec11a/osteolectin is an osteogenic growth factor that promotes the maintenance of the adult skeleton

    Rui Yue, Bo Shen, Sean J Morrison
    Research Article

    Bone marrow stromal cells maintain the adult skeleton by forming osteoblasts throughout life that regenerate bone and repair fractures. We discovered that subsets of these stromal cells, osteoblasts, osteocytes, and hypertrophic chondrocytes secrete a C-type lectin domain protein, Clec11a, which promotes osteogenesis. Clec11a-deficient mice appeared developmentally normal and had normal hematopoiesis but reduced limb and vertebral bone. Clec11a-deficient mice exhibited accelerated bone loss during aging, reduced bone strength, and delayed fracture healing. Bone marrow stromal cells from Clec11a-deficient mice showed impaired osteogenic differentiation, but normal adipogenic and chondrogenic differentiation. Recombinant Clec11a promoted osteogenesis by stromal cells in culture and increased bone mass in osteoporotic mice in vivo. Recombinant human Clec11a promoted osteogenesis by human bone marrow stromal cells in culture and in vivo. Clec11a thus maintains the adult skeleton by promoting the differentiation of mesenchymal progenitors into mature osteoblasts. In light of this, we propose to call this factor Osteolectin.

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