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

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 alpha-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. Matrix stiffening is a quintessential feature of aged tissues. Authors show that an aged (stiff) matrix epigenetically represses the gene encoding the longevity factor, alpha-Klotho, resulting in chondrocyte dysfunction, a leading cause of osteoarthritis.

Automated summary

Matrix stiffening is a key characteristic of aged tissues. In this study, the authors found that an aged (stiff) matrix causes epigenetic repression of the gene encoding alpha-Klotho, a longevity factor, leading to chondrocyte dysfunction, which is a major cause of osteoarthritis. Exposing aged chondrocytes to a soft matrix restores a more youthful phenotype and enhances cartilage integrity. These findings highlight the importance of age-related biophysical alterations in extracellular matrix and have implications for the broader field of aging research.