NFATc1 marks articular cartilage progenitors and negatively determines articular chondrocyte differentiation

  1. Fan Zhang
  2. Yuanyuan Wang
  3. Ying Zhao
  4. Manqi Wang
  5. Bin Zhao
  6. Bin Zhou
  7. Xianpeng Ge  Is a corresponding author
  1. Xuan Wu Hospital of the Capital Medical University, China
  2. Central South University, China
  3. Albert Einstein College of Medicine, United States
  4. Chinese Academy of Sciences, China

Abstract

The origin and differentiation mechanism of articular chondrocytes remain poorly understood. Broadly, the difference in developmental mechanisms of articular and growth-plate cartilage is still less elucidated. Here, we identified that the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) is a crucial regulator of articular, but not growth-plate, chondrocyte differentiation during development. At the early stage of mouse knee development (embryonic day 13.5), NFATc1-expressing cells were mainly located in the flanking region of the joint interzone. With development, NFATc1-expressing cells generated almost all articular chondrocytes, but not chondrocytes in limb growth-plate primordium. NFATc1-expressing cells displayed prominent capacities for colony formation and multipotent differentiation. Transcriptome analyses revealed a set of characteristic genes in NFATc1-enriched articular cartilage progenitors. Strikingly, the expression of NFATc1 was diminished with articular chondrocyte differentiation and suppressing NFATc1 expression in articular cartilage progenitors was sufficient to induce spontaneous chondrogenesis while overexpressing NFATc1 suppresses chondrogenesis. Mechanistically, NFATc1 negatively regulated the transcriptional activity of the Col2a1 gene. Thus, our results reveal that NFATc1 characterizes articular, but not growth-plate, cartilage progenitors during development and negatively determines articular chondrocyte differentiation at least partly through regulating COL2A1 gene transcription.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file. The raw datasets of RNA-seq are available in Dryad Digital Repository (doi:10.5061/dryad.2fqz612rw).

The following data sets were generated

Article and author information

Author details

  1. Fan Zhang

    Xuan Wu Hospital of the Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yuanyuan Wang

    Xuan Wu Hospital of the Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ying Zhao

    Xuan Wu Hospital of the Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Manqi Wang

    Central South University, Changsha, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Bin Zhao

    Department of Genetics, Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Bin Zhou

    Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Xianpeng Ge

    Xuan Wu Hospital of the Capital Medical University, Beijing, China
    For correspondence
    xianpeng.ge@xwhosp.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1291-2096

Funding

National Natural Science Foundation of China (81100767)

  • Xianpeng Ge

Beijing Natural Science Foundation (5222008)

  • Xianpeng Ge

Natural Science Foundation of Capital Medical University (1220010146)

  • Xianpeng Ge

Outstanding Young Researcher Award of Beijing Municipality (N/A)

  • Xianpeng Ge

Outstanding Researcher Award of Xuanwu Hospital Capital Medical University (N/A)

  • Xianpeng Ge

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

Reviewing Editor

  1. Di Chen, Chinese Academy of Sciences, China

Ethics

Animal experimentation: All animal studies followed the recommendations in the Guide for the Care and Use of Laboratory Animals of the U.S. National Institutes of Health and were approved by Institutional Animal Care and Use Committee at Capital Medical University (protocol #: AEEI-2022-036).

Version history

  1. Preprint posted: June 29, 2022 (view preprint)
  2. Received: July 3, 2022
  3. Accepted: February 12, 2023
  4. Accepted Manuscript published: February 15, 2023 (version 1)
  5. Version of Record published: April 5, 2023 (version 2)

Copyright

© 2023, Zhang 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. Fan Zhang
  2. Yuanyuan Wang
  3. Ying Zhao
  4. Manqi Wang
  5. Bin Zhao
  6. Bin Zhou
  7. Xianpeng Ge
(2023)
NFATc1 marks articular cartilage progenitors and negatively determines articular chondrocyte differentiation
eLife 12:e81569.
https://doi.org/10.7554/eLife.81569

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https://doi.org/10.7554/eLife.81569

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