Previously, we reported that persistent DNA damage accelerates ageing of the spine, but the mechanisms behind this process are not well understood. Ataxia telangiectasia mutated (ATM) is a protein kinase involved in the DNA damage response, which controls cell fate, including cell death. To test the role of ATM in the human intervertebral disc, we exposed human nucleus pulposus (hNP) cells directly to the DNA damaging agent cisplatin. Cisplatin-treated hNP cells exhibited rapid phosphorylation of ATM and subsequent increased NF-κB activation, aggrecanolysis, decreased total proteoglycan production and increased expression of markers of senescence, including p21, γH2AX and SA-ß-gal. Treating cisplatin-exposed hNP cells with an ATM-specific inhibitor negated these effects. In addition, genetic reduction of ATM reduced disc cellular senescence and matrix proteoglycan loss in the progeroid Ercc1−/∆ mouse model of accelerated ageing. These findings suggest that activation of ATM signalling under persistent genotoxic stress promotes disc cellular senescence and matrix homeostatic perturbation. Thus, the ATM signalling pathway represents a therapeutic target to delay the progression of age-associated spine pathologies.
Bibliographical noteFunding Information:
The work was supported by NIH AG044376 to NV and PO1AG043376, R01AG063543, R56AG059676, R56AG059675, P01AG062413 and U19AG056278 to PDR and LJN. We would like to acknowledge the NIH supported microscopy resources in the Center for Biologic Imaging at the University of Pittsburgh, specifically, the confocal microscope supported by grant number 1S10OD019973-01. We would like to thank the Ferguson laboratory administrative and research staff for their support. The authors would like to thank Jessa Darwin for editorial assistance on the manuscript.
- accelerated ageing
- endogenous DNA damage
- intervertebral disc degeneration
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't