纺神星
软骨细胞
细胞生物学
细胞外基质
表观遗传学
软骨
生物
DNA甲基化
衰老
机械敏感通道
基因表达
遗传学
解剖
基因
离子通道
受体
肾
作者
Hirotaka Iijima,Gabrielle G. 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
标识
DOI:10.1038/s41467-022-35359-2
摘要
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.
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