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

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 and Fabrisia Ambrosio ()
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Hirotaka Iijima: University of Pittsburgh
Gabrielle Gilmer: University of Pittsburgh
Kai Wang: University of Pittsburgh
Allison C. Bean: University of Pittsburgh
Yuchen He: University of Pittsburgh
Hang Lin: 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

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-022-35359-2

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