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Oxidative stress-induced DNA damage and repair in primary human osteoarthritis chondrocytes: focus on IKKα and the DNA Mismatch Repair System
- Source :
- Free Radical Biology and Medicine. 166:212-225
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
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.
- Subjects :
- Osteoarthritis (OA)
0301 basic medicine
Senescence
DNA Repair
DNA damage
IκB kinase
Oxidative phosphorylation
Biology
medicine.disease_cause
DNA Mismatch Repair
Biochemistry
03 medical and health sciences
Chondrocytes
0302 clinical medicine
Physiology (medical)
Osteoarthritis
medicine
Humans
Microsatellite instability (MSI)
Oxidative stress (OS)
Chondrocyte aging
Mismatch repair (MMR)
Gene knockdown
DNA damage Response (DDR)
Microsatellite instability
Oxidative Stre
Hydrogen Peroxide
Chondrocyte
medicine.disease
I-kappa B Kinase
Cell biology
Oxidative Stress
030104 developmental biology
DNA mismatch repair
030217 neurology & neurosurgery
Oxidative stress
DNA Damage
Human
Subjects
Details
- ISSN :
- 08915849
- Volume :
- 166
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine
- Accession number :
- edsair.doi.dedup.....9e37853cdee188f1cfddd494a2bf4b63