Oxidative stress-induced DNA damage and repair in primary human osteoarthritis chondrocytes: focus on IKK? and the DNA Mismatch Repair System

During osteoarthritis development, chondrocytes are subjected to a functional derangement. This increases their susceptibility to stressful conditions such as oxidative stress, a characteristic of the aging tissue, which can further provoke extrinsic senescence by DNA damage responses. It was previously observed that I?B kinase ? knockdown increases the replicative potential of primary human OA chondrocytes cultured in monolayer and the survival of the same cells undergoing hypertrophic-like differentiation in 3-D. In this paper we investigated whether IKK? knockdown could modulate oxidative stress-induced senescence of OA chondrocytes undergoing a DDR and particularly the involvement in this process of the DNA mismatch repair system, the principal mechanism for repair of replicative and recombinational errors, devoted to genomic stability maintenance in actively replicating cells. This repair system is also implicated in oxidative stress-mediated DNA damage repair. We analyzed microsatellite instability and expression of the mismatch repair components in human osteoarthritis chondrocytes after IKK? knockdown and H2O2 exposure. Only low MSI levels and incidence were detected and exclusively in IKK? proficient cells. Moreover, we found that IKK? proficient and deficient chondrocytes differently regulated MMR proteins after oxidative stress, both at mRNA and protein level, suggesting a reduced susceptibility of IKK? deficient cells. Our data suggest an involvement of the MMR system in the response to oxidative stress that tends to be more efficient in IKK?KD cells. This argues for a partial contribution of the MMR system to the better ability to recover DNA damage already observed in these cells.