Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs.
Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs.
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DOI：
10.1016/j.mad.2012.11.002
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发表时间：
2013-01
影响因子：
5.3
通讯作者：
Vo, Nam V.
中科院分区：
文献类型：
--
作者：
Nasto, Luigi A.;Wang, Dong;Robinson, Andria R.;Clauson, Cheryl L.;Ngo, Kevin;Dong, Qing;Roughley, Peter;Epperly, Michael;Huq, Saiful M.;Pola, Enrico;Sowa, Gwendolyn;Robbins, Paul D.;Kang, James;Niedernhofer, Laura J.;Vo, Nam V.
椎间盘退行性变(IDD)是慢性下腰痛等致衰弱脊柱疾病的主要原因。老龄化是IDD的最大危险因素。此前，我们在一种由关键DNA修复酶表达减少引起的孕激素综合征小鼠模型中证明了IDD。这导致我们假设DNA损伤促进了IDD。为了验证我们的假设，我们将成年野生型(Wt)和DNA修复缺陷的ERCC1−/Δ小鼠长期暴露于癌症治疗剂机械氯乙胺(MEC)或电离辐射(IR)中，以诱导DNA损伤，并测量其对椎间盘结构的影响。蛋白多糖是椎间盘的主要结构基质成分，与未处理的对照组相比，在MEC和IR暴露的动物的椎间盘中，蛋白多糖减少了3-5倍。蛋白水解酶ADAMTS4和aggrecan蛋白水解段的表达显著增加。此外，与未经处理的对照组相比，经MEC和IR处理的椎间盘中新的PG合成减少了2-3倍。治疗组小鼠关节盘细胞衰老和细胞凋亡率均增加。这种影响在DNA修复缺陷的ERCC1−/Δ小鼠中比在Wt胎中更严重。Wt小鼠脊椎的局部照射也引起了类似的PG减少。这些数据表明，基因毒性应激导致与IDD相关的退行性变化。
Intervertebral disc degeneration (IDD) is the leading cause of debilitating spinal disorders such as chronic lower back pain. Aging is the greatest risk factor for IDD. Previously, we demonstrated IDD in a murine model of a progeroid syndrome caused by reduced expression of a key DNA repair enzyme. This led us to hypothesize that DNA damage promotes IDD. To test our hypothesis, we chronically exposed adult wild-type (Wt) and DNA repair-deficient Ercc1−/Δ mice to the cancer therapeutic agent mechlorethamine (MEC) or ionization radiation (IR) to induce DNA damage and measured the impact on disc structure. Proteoglycan, a major structural matrix constituent of the disc, was reduced 3-5x in the discs of MEC- and IR-exposed animals compared to untreated controls. Expression of the protease ADAMTS4 and aggrecan proteolytic fragments were significantly increased. Additionally, new PG synthesis was reduced 2-3x in MEC- and IR-treated discs compared to untreated controls. Both cellular senescence and apoptosis were increased in discs of treated animals. The effects were more severe in the DNA repair-deficient Ercc1−/Δ mice than in Wt littermates. Local irradiation of the vertebra in Wt mice elicited a similar reduction in PG. These data demonstrate that genotoxic stress drives degenerative changes associated with IDD.
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影响因子：
3
作者：
Bibby, SRS;Jones, DA;Urban, JPG
通讯作者：
Urban, JPG
影响因子：
3
作者：
HART, LG;DEYO, RA;CHERKIN, DC
通讯作者：
CHERKIN, DC
DOI：
10.1016/0304-4165(86)90306-5
发表时间：
1986-09-04
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
FARNDALE, RW;BUTTLE, DJ;BARRETT, AJ
通讯作者：
BARRETT, AJ
影响因子：
3
作者：
BATTIE, MC;VIDEMAN, T;KOSKENVUO, M
通讯作者：
KOSKENVUO, M
影响因子：
4.8
作者：
Hong, Eun-Hee;Lee, Su-Jae;Hwang, Sang-Gu
通讯作者：
Hwang, Sang-Gu