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Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

Author

Listed:
  • Hirotaka Iijima

    (University of Pittsburgh
    Japan Society for the Promotion of Science
    Nagoya University)

  • Gabrielle Gilmer

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh
    Schoen Adams Research Institute at Spaulding)

  • Kai Wang

    (University of Pittsburgh
    Schoen Adams Research Institute at Spaulding
    Harvard Medical School)

  • Allison C. Bean

    (University of Pittsburgh
    University of Pittsburgh)

  • Yuchen He

    (University of Pittsburgh)

  • Hang Lin

    (University of Pittsburgh
    University of Pittsburgh
    University of Pittsburgh)

  • Wan-Yee Tang

    (University of Pittsburgh School of Public Health)

  • Daniel Lamont

    (University of Pittsburgh)

  • Chia Tai

    (Kyoto University)

  • Akira Ito

    (Kyoto University)

  • Jeffrey J. Jones

    (Beckman Institute, California Institute of Technology)

  • Christopher Evans

    (Mayo Clinic)

  • Fabrisia Ambrosio

    (University of Pittsburgh
    University of Pittsburgh
    Schoen Adams Research Institute at Spaulding
    Harvard Medical School)

Abstract

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.

Suggested Citation

  • Hirotaka Iijima & Gabrielle Gilmer & Kai Wang & Allison C. Bean & Yuchen He & Hang Lin & Wan-Yee Tang & Daniel Lamont & Chia Tai & Akira Ito & Jeffrey J. Jones & Christopher Evans & Fabrisia Ambrosio, 2023. "Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35359-2
    DOI: 10.1038/s41467-022-35359-2
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    References listed on IDEAS

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    1. I. Bronshtein & E. Kepten & I. Kanter & S. Berezin & M. Lindner & Abena B. Redwood & S Mai & S. Gonzalo & R. Foisner & Y. Shav-Tal & Y. Garini, 2015. "Loss of lamin A function increases chromatin dynamics in the nuclear interior," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
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    3. Nathalie Percie du Sert & Viki Hurst & Amrita Ahluwalia & Sabina Alam & Marc T Avey & Monya Baker & William J Browne & Alejandra Clark & Innes C Cuthill & Ulrich Dirnagl & Michael Emerson & Paul Garne, 2020. "The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research," PLOS Biology, Public Library of Science, vol. 18(7), pages 1-12, July.
    4. Qian Yuan & Qian Ren & Li Li & Huishi Tan & Meizhi Lu & Yuan Tian & Lu Huang & Boxin Zhao & Haiyan Fu & Fan Fan Hou & Lili Zhou & Youhua Liu, 2022. "A Klotho-derived peptide protects against kidney fibrosis by targeting TGF-β signaling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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