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

Simona Neri, Serena Guidotti, Carla Bini, Susi Pelotti, Stefania D'Adamo, Manuela Minguzzi, Daniela Platano, Spartaco Santi, Erminia Mariani, Luca Cattini, Rosa Maria Borzì

Research output: Contribution to journalArticlepeer-review

Abstract

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 IκB kinase α 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 IKKα 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 IKKα knockdown and H2O2 exposure. Only low MSI levels and incidence were detected and exclusively in IKKα proficient cells. Moreover, we found that IKKα proficient and deficient chondrocytes differently regulated MMR proteins after oxidative stress, both at mRNA and protein level, suggesting a reduced susceptibility of IKKα deficient cells. Our data suggest an involvement of the MMR system in the response to oxidative stress that tends to be more efficient in IKKαKD cells. This argues for a partial contribution of the MMR system to the better ability to recover DNA damage already observed in these cells.

Original languageEnglish
Pages (from-to)212-225
Number of pages14
JournalFree Radical Biology and Medicine
Volume166
DOIs
Publication statusE-pub ahead of print - Feb 23 2021

Keywords

  • Chondrocyte aging
  • DNA damage Response (DDR)
  • Microsatellite instability (MSI)
  • Mismatch repair (MMR)
  • Osteoarthritis (OA)
  • Oxidative stress (OS)

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