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Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration
Yingchao Han1,2,3, Chao-Ming Zhou3, Hongxing Shen1
1Department of Spine Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
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, γH2 AX 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.
Insights
Persistent DNA damage accelerates spine aging via the ATM signaling pathway. Inhibiting ATM reduces cellular senescence and matrix loss, suggesting it as a therapeutic target for age-related spine conditions.
Area of Science:
- Biochemistry
- Cell Biology
- Gerontology
Background:
- Persistent DNA damage is linked to accelerated spine aging.
- The precise mechanisms driving this process remain unclear.
- Ataxia telangiectasia mutated (ATM) kinase is crucial in DNA damage response and cell fate.
- ATM's role in human intervertebral disc aging requires investigation.
Purpose of the Study:
- To investigate the role of ATM signaling in human nucleus pulposus (hNP) cells under genotoxic stress.
- To determine if ATM activation contributes to cellular senescence and matrix degradation in intervertebral discs.
- To evaluate ATM as a potential therapeutic target for age-associated spine pathologies.
Main Methods:
- Exposed human nucleus pulposus (hNP) cells to the DNA damaging agent cisplatin.
- Assessed ATM phosphorylation, NF-κB activation, and matrix component changes (aggrecanolysis, proteoglycan production).
- Evaluated senescence markers (p21, γH2AX, SA-β-gal) in treated cells.
- Utilized an ATM-specific inhibitor and genetic reduction of ATM in an accelerated aging mouse model (Ercc1-/Δ).
Main Results:
- Cisplatin treatment induced ATM phosphorylation, NF-κB activation, aggrecanolysis, and decreased proteoglycan production in hNP cells.
- Increased expression of senescence markers (p21, γH2AX, SA-β-gal) was observed post-cisplatin exposure.
- ATM inhibition reversed cisplatin-induced senescence and matrix perturbations.
- Genetic ATM reduction mitigated disc cellular senescence and matrix proteoglycan loss in the Ercc1-/Δ mouse model.
Conclusions:
- ATM signaling activation under persistent genotoxic stress promotes intervertebral disc cellular senescence.
- ATM pathway activation contributes to matrix homeostatic disruption in aging discs.
- The ATM signaling pathway is a promising therapeutic target for delaying age-associated spine pathologies.
