Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration.

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.

journal_name

Aging Cell

journal_title

Aging cell

authors

Han Y,Zhou CM,Shen H,Tan J,Dong Q,Zhang L,McGowan SJ,Zhao J,Sowa GA,Kang JD,Niedernhofer LJ,Robbins PD,Vo NN

doi

10.1111/acel.13162

subject

Has Abstract

pub_date

2020-07-01 00:00:00

pages

e13162

issue

7

eissn

1474-9718

issn

1474-9726

journal_volume

19

pub_type

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