1. Stem Cells and Regenerative Medicine
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Long non-coding RNA GRASLND enhances chondrogenesis via suppression of interferon type II signaling pathway

  1. Nguyen PT Huynh
  2. Catherine C Gloss
  3. Jeremiah Lorentz
  4. Ruhang Tang
  5. Jonathan M Brunger
  6. Audrey McAlinden
  7. Bo Zhang
  8. Farshid Guilak  Is a corresponding author
  1. Washington University in St Louis, United States
  2. Vanderbilt University, United States
Research Article
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Cite this article as: eLife 2020;9:e49558 doi: 10.7554/eLife.49558

Abstract

The roles of long noncoding RNAs (lncRNAs) in musculoskeletal development, disease, and regeneration remain poorly understood. Here, we identified the novel lncRNA GRASLND (originally named RNF144A-AS1) as a regulator of mesenchymal stem cell (MSC) chondrogenesis. GRASLND, a primate-specific lncRNA, is upregulated during MSC chondrogenesis and appears to act directly downstream of SOX9, but not TGF-b3. We showed that the silencing of GRASLND resulted in lower accumulation of cartilage-like extracellular matrix in a pellet assay, while GRASLND overexpression – either via transgene ectopic expression or by endogenous activation via CRISPR-dCas9-VP64 – significantly enhanced cartilage matrix production. GRASLND acts to inhibit IFN-γ by binding to EIF2AK2, and we further demonstrated that GRASLND exhibits a protective effect in engineered cartilage against interferon type II. Our results indicate an important role of GRASLND in regulating stem cell chondrogenesis, as well as its therapeutic potential in the treatment of cartilage-related diseases, such as osteoarthritis.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE129985.

The following data sets were generated
The following previously published data sets were used

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Author details

  1. Nguyen PT Huynh

    Orthopaedic Surgery, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7254-1645

  2. Catherine C Gloss

    Orthopaedic Surgery, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Jeremiah Lorentz

    Orthopaedic Surgery, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Ruhang Tang

    Orthopaedic Surgery, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Jonathan M Brunger

    Biomedical Engineering, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Audrey McAlinden

    Orthopaedic Surgery, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Bo Zhang

    Department of Developmental Biology, Washington University in St Louis, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Farshid Guilak

    Orthopaedics, Washington University in St Louis, St Louis, United States
    For correspondence
    guilak@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7380-0330

Funding

Arthritis Foundation

  • Farshid Guilak

Nancy Taylor Foundation for Chronic Diseases

  • Farshid Guilak

National Institutes of Health

  • Farshid Guilak

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

Reviewing Editor

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

Publication history

  1. Received: June 21, 2019
  2. Accepted: March 21, 2020
  3. Accepted Manuscript published: March 23, 2020 (version 1)
  4. Version of Record published: May 6, 2020 (version 2)

Copyright

© 2020, Huynh 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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