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

Yingchao Han; Chao Ming Zhou; Hongxing Shen; Jun Tan; Qing Dong; Lei Zhang; Sara J. McGowan; Jing Zhao; Gwendolyn A. Sowa; James D. Kang; Laura J. Niedernhofer; Paul D. Robbins; Nam N. Vo

doi:10.1111/acel.13162

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

Yingchao Han, Chao Ming Zhou, Hongxing Shen, Jun Tan, Qing Dong, Lei Zhang, Sara J. McGowan, Jing Zhao, Gwendolyn A. Sowa, James D. Kang, Laura J. Niedernhofer, Paul D. Robbins, Nam N. Vo

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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, 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.

Original language	English (US)
Article number	e13162
Journal	Aging cell
Volume	19
Issue number	7
DOIs	https://doi.org/10.1111/acel.13162
State	Published - Jul 1 2020

Bibliographical note

Funding 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.

Publisher Copyright:
© 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Keywords

ATM
NF-κB
ROS
accelerated ageing
endogenous DNA damage
intervertebral disc degeneration

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10.1111/acel.13162

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title = "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, 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.",

keywords = "ATM, NF-κB, ROS, accelerated ageing, endogenous DNA damage, intervertebral disc degeneration",

author = "Yingchao Han and Zhou, {Chao Ming} and Hongxing Shen and Jun Tan and Qing Dong and Lei Zhang and McGowan, {Sara J.} and Jing Zhao and Sowa, {Gwendolyn A.} and Kang, {James D.} and Niedernhofer, {Laura J.} and Robbins, {Paul D.} and Vo, {Nam N.}",

note = "Funding 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. Publisher Copyright: {\textcopyright} 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",

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doi = "10.1111/acel.13162",

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T1 - Attenuation of ataxia telangiectasia mutated signalling mitigates age-associated intervertebral disc degeneration

AU - Han, Yingchao

AU - Zhou, Chao Ming

AU - Shen, Hongxing

AU - Tan, Jun

AU - Dong, Qing

AU - Zhang, Lei

AU - McGowan, Sara J.

AU - Zhao, Jing

AU - Sowa, Gwendolyn A.

AU - Kang, James D.

AU - Niedernhofer, Laura J.

AU - Robbins, Paul D.

AU - Vo, Nam N.

N1 - Funding 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. Publisher Copyright: © 2020 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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Y1 - 2020/7/1

N2 - 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.

AB - 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.

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KW - NF-κB

KW - ROS

KW - accelerated ageing

KW - endogenous DNA damage

KW - intervertebral disc degeneration

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DO - 10.1111/acel.13162

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JO - Aging cell

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ER -

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

Abstract

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