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

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 carti

SUBMITTER: Iijima H 

PROVIDER: S-EPMC9832042 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature