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Lipid availability determines fate of skeletal progenitor cells via SOX9

Author

Listed:
  • Nick van Gastel

    (KU Leuven
    KU Leuven
    Harvard University
    Harvard University)

  • Steve Stegen

    (KU Leuven
    KU Leuven)

  • Guy Eelen

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Sandra Schoors

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Aurélie Carlier

    (KU Leuven
    KU Leuven
    University of Liège
    Maastricht University)

  • Veerle W. Daniëls

    (KU Leuven
    Harvard Medical School)

  • Ninib Baryawno

    (Harvard University
    Harvard University
    Massachusetts General Hospital
    Karolinska Institutet)

  • Dariusz Przybylski

    (Brandeis University)

  • Maarten Depypere

    (KU Leuven
    KU Leuven)

  • Pieter-Jan Stiers

    (KU Leuven
    KU Leuven)

  • Dennis Lambrechts

    (KU Leuven
    KU Leuven
    KU Leuven)

  • Riet Van Looveren

    (KU Leuven)

  • Sophie Torrekens

    (KU Leuven)

  • Azeem Sharda

    (Harvard University
    Harvard University
    Massachusetts General Hospital)

  • Patrizia Agostinis

    (KU Leuven)

  • Diether Lambrechts

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Frederik Maes

    (KU Leuven
    KU Leuven)

  • Johan V. Swinnen

    (KU Leuven)

  • Liesbet Geris

    (KU Leuven
    KU Leuven
    University of Liège)

  • Hans Van Oosterwyck

    (KU Leuven
    KU Leuven)

  • Bernard Thienpont

    (KU Leuven
    Center for Cancer Biology, VIB)

  • Peter Carmeliet

    (KU Leuven
    Center for Cancer Biology, VIB)

  • David T. Scadden

    (Harvard University
    Harvard University
    Massachusetts General Hospital)

  • Geert Carmeliet

    (KU Leuven
    KU Leuven)

Abstract

The avascular nature of cartilage makes it a unique tissue1–4, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.

Suggested Citation

  • Nick van Gastel & Steve Stegen & Guy Eelen & Sandra Schoors & Aurélie Carlier & Veerle W. Daniëls & Ninib Baryawno & Dariusz Przybylski & Maarten Depypere & Pieter-Jan Stiers & Dennis Lambrechts & Rie, 2020. "Lipid availability determines fate of skeletal progenitor cells via SOX9," Nature, Nature, vol. 579(7797), pages 111-117, March.
    • Handle: RePEc:nat:nature:v:579:y:2020:i:7797:d:10.1038_s41586-020-2050-1
    DOI: 10.1038/s41586-020-2050-1
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    Cited by:

    1. Tammy Liu & Gerd Melkus & Tim Ramsay & Adnan Sheikh & Odette Laneuville & Guy Trudel, 2023. "Bone marrow adiposity modulation after long duration spaceflight in astronauts," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Aaron Warren & Ryan M. Porter & Olivia Reyes-Castro & Md Mohsin Ali & Adriana Marques-Carvalho & Ha-Neui Kim & Landon B. Gatrell & Ernestina Schipani & Intawat Nookaew & Charles A. O’Brien & Roy Morel, 2023. "The NAD salvage pathway in mesenchymal cells is indispensable for skeletal development in mice," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Caojie Liu & Qiuchan Xiong & Qiwen Li & Weimin Lin & Shuang Jiang & Danting Zhang & Yuan Wang & Xiaobo Duan & Ping Gong & Ning Kang, 2022. "CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Zhe Gong & Jinjin Zhu & Junxin Chen & Fan Feng & Haitao Zhang & Zheyuan Zhang & Chenxin Song & Kaiyu Liang & Shuhui Yang & Shunwu Fan & Xiangqian Fang & Shuying Shen, 2023. "CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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