Open AccessAttenuation of ataxia telangiectasia mutated signalling mitigates age‐associated intervertebral disc degeneration
Author(s) -
Han Yingchao,
Zhou ChaoMing,
Shen Hongxing,
Tan Jun,
Dong Qing,
Zhang Lei,
McGowan Sara J.,
Zhao Jing,
Sowa Gwendolyn A.,
Kang James D.,
Niedernhofer Laura J.,
Robbins Paul D.,
Vo Nam N.
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13162
Subject(s) - ataxia telangiectasia , senescence , biology , dna damage , microbiology and biotechnology , telomere , cisplatin , kinase , cancer research , ageing , programmed cell death , apoptosis , genetics , dna , chemotherapy
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, γH 2 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.