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

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.

Data availability

Source data files have been provided for all figures.

Article and author information

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).

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.

Metrics

  • 3,808
    views
  • 652
    downloads
  • 72
    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. 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

Share this article

https://doi.org/10.7554/eLife.42274

Further reading

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Joseph A Bisson, Miriam Gordillo ... Todd Evans
    Research Article

    Haploinsufficiency for GATA6 is associated with congenital heart disease (CHD) with variable comorbidity of pancreatic or diaphragm defects, although the etiology of disease is not well understood. Here, we used cardiac directed differentiation from human embryonic stem cells (hESCs) as a platform to study GATA6 function during early cardiogenesis. GATA6 loss-of-function hESCs had a profound impairment in cardiac progenitor cell (CPC) specification and cardiomyocyte (CM) generation due to early defects during the mesendoderm and lateral mesoderm patterning stages. Profiling by RNA-seq and CUT&RUN identified genes of the WNT and BMP programs regulated by GATA6 during early mesoderm patterning. Furthermore, interactome analysis detected GATA6 binding with developmental transcription factors and chromatin remodelers, suggesting cooperative regulation of cardiac lineage gene accessibility. We show that modulating WNT and BMP inputs during the first 48 hr of cardiac differentiation is sufficient to partially rescue CPC and CM defects in GATA6 heterozygous and homozygous mutant hESCs. This study provides evidence of the regulatory functions for GATA6 directing human precardiac mesoderm patterning during the earliest stages of cardiogenesis to further our understanding of haploinsufficiency causing CHD and the co-occurrence of cardiac and other organ defects caused by human GATA6 mutations.

    1. Cell Biology
    2. Stem Cells and Regenerative Medicine
    Liyi Wang, Shiqi Liu ... Tizhong Shan
    Research Article

    Conjugated linoleic acids (CLAs) can serve as a nutritional intervention to regulate quality, function, and fat infiltration in skeletal muscles, but the specific cytological mechanisms remain unknown. Here, we applied single-nucleus RNA-sequencing (snRNA-seq) to characterize the cytological mechanism of CLAs regulates fat infiltration in skeletal muscles based on pig models. We investigated the regulatory effects of CLAs on cell populations and molecular characteristics in pig muscles and found CLAs could promote the transformation of fast glycolytic myofibers into slow oxidative myofibers. We also observed three subpopulations including SCD+/DGAT2+, FABP5+/SIAH1+, and PDE4D+/PDE7B+ subclusters in adipocytes and CLAs could increase the percentage of SCD+/DGAT2+ adipocytes. RNA velocity analysis showed FABP5+/SIAH1+ and PDE4D+/PDE7B+ adipocytes could differentiate into SCD+/DGAT2+ adipocytes. We further verified the differentiated trajectory of mature adipocytes and identified PDE4D+/PDE7B+ adipocytes could differentiate into SCD+/DGAT2+ and FABP5+/SIAH1+ adipocytes by using high intramuscular fat (IMF) content Laiwu pig models. The cell-cell communication analysis identified the interaction network between adipocytes and other subclusters such as fibro/adipogenic progenitors (FAPs). Pseudotemporal trajectory analysis and RNA velocity analysis also showed FAPs could differentiate into PDE4D+/PDE7B+ preadipocytes and we discovered the differentiated trajectory of preadipocytes into mature adipocytes. Besides, we found CLAs could promote FAPs differentiate into SCD+/DGAT2+ adipocytes via inhibiting c-Jun N-terminal kinase (JNK) signaling pathway in vitro. This study provides a foundation for regulating fat infiltration in skeletal muscles by using nutritional strategies and provides potential opportunities to serve pig as an animal model to study human fat infiltrated diseases.