DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes.

Abstract

The initiation/progression factors of osteoarthritic (OA) cartilage degeneration and the involved biological mechanisms remain rather enigmatic. One core reason for this might be a cellular senescence-like phenotype of OA chondrocytes, which might show a fundamentally different behavior pattern unexpected from the biological mechanism established in young cells.
This study was designed to investigate one core property of senescent cells, the heterogeneity of gene expression, in OA chondrocytes by double-labeling immunolocalization using two genes (vimentin, S-100 protein) as surrogates, which are constitutively expressed by (normal) chondrocytes. The level of genomic DNA damage in OA chondrocytes was compared to normal chondrocytes and in vitro experiments designed to demonstrate that stochastic genomic DNA damage is able to induce heterogeneity of gene expression in chondrocytes.
We show a significantly increased heterogeneity of gene expression for vimentin and S-100 protein as well as a significantly increased genomic DNA damage in the OA compared to normal chondrocytes, whereas no evidence of critical telomere shortening was found. In vitro experiments demonstrated that stochastic genomic DNA damage induced by increased oxidative or genotoxic stress is able to induce the heterogeneity in gene expression found in the OA cells in situ.
Our results suggest that OA chondrocytes show a special form of age-related cell degeneration, "progressive/stress-induced senescence", progressing over time due to accumulated DNA damage and subsequent chaotic gene activation pattern. This promotes increased malfunctioning of the cells and finally the loss of their capacity to keep up cell and tissue homeostasis, i.e., prevent OA.