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DOT1L safeguards cartilage homeostasis and protects against osteoarthritis

Author

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  • Silvia Monteagudo

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven)

  • Frederique M. F. Cornelis

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven)

  • Carolina Aznar-Lopez

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven)

  • Ploi Yibmantasiri

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven)

  • Laura-An Guns

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven)

  • Peter Carmeliet

    (Laboratory of Angiogenesis and Vascular Metabolism, KU Leuven
    Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB)

  • Frédéric Cailotto

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
    CNRS-Université de Lorraine, UMR7365, Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Biopôle de l’Université de Lorraine)

  • Rik J. Lories

    (Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven
    University Hospitals)

Abstract

Osteoarthritis is the most prevalent and crippling joint disease, and lacks curative treatment, as the underlying molecular basis is unclear. Here, we show that DOT1L, an enzyme involved in histone methylation, is a master protector of cartilage health. Loss of DOT1L disrupts the molecular signature of healthy chondrocytes in vitro and causes osteoarthritis in mice. Mechanistically, the protective function of DOT1L is attributable to inhibition of Wnt signalling, a pathway that when hyper-activated can lead to joint disease. Unexpectedly, DOT1L suppresses Wnt signalling by inhibiting the activity of sirtuin-1 (SIRT1), an important regulator of gene transcription. Inhibition of SIRT1 protects against osteoarthritis triggered by loss of DOT1L activity. Modulating the DOT1L network might therefore be a therapeutic approach to protect the cartilage against osteoarthritis.

Suggested Citation

  • Silvia Monteagudo & Frederique M. F. Cornelis & Carolina Aznar-Lopez & Ploi Yibmantasiri & Laura-An Guns & Peter Carmeliet & Frédéric Cailotto & Rik J. Lories, 2017. "DOT1L safeguards cartilage homeostasis and protects against osteoarthritis," Nature Communications, Nature, vol. 8(1), pages 1-12, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15889
    DOI: 10.1038/ncomms15889
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    Cited by:

    1. Ana Escribano-Núñez & Frederique M. F. Cornelis & Astrid Roover & An Sermon & Frédéric Cailotto & Rik J. Lories & Silvia Monteagudo, 2024. "IGF1 drives Wnt-induced joint damage and is a potential therapeutic target for osteoarthritis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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