Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype.
Senescent intervertebral disc cells exhibit perturbed matrix homeostasis phenotype.
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DOI：
10.1016/j.mad.2017.08.007
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发表时间：
2017-09
影响因子：
5.3
通讯作者：
Vo N
中科院分区：
文献类型：
--
作者：
Ngo K;Patil P;McGowan SJ;Niedernhofer LJ;Robbins PD;Kang J;Sowa G;Vo N
衰老大大增加了椎间盘退变（IDD）的风险，这是由于椎间盘基质蛋白聚糖（PG）合成减少和降解增强而导致的蛋白聚糖损失。椎间盘基质PG动态平衡如何随着年龄的增长而受到干扰尚不清楚。本研究的目的是确定细胞衰老是否是这种扰动的来源。我们证明了DNA修复缺陷Ercc1−/Δ小鼠早衰症小鼠模型中椎间盘细胞衰老显著增加。在这些加速衰老的小鼠中，椎间盘细胞衰老的增加与椎间盘PG的快速丢失密切相关。我们还使用体外细胞培养模型系统直接检测了氧化损伤诱导的衰老人类细胞中PG的稳态。通过生长停滞、衰老相关β-半乳糖苷酶活性、γ - h2ax焦点和衰老相关分泌表型的获得，证实了过氧化氢处理的人椎间盘细胞的衰老。衰老的人椎间盘细胞也表现出基质PG稳态紊乱，这可以通过它们合成新基质PG的能力下降和椎间盘主要基质PG聚集蛋白的降解增强来证明。我们在体内和体外的研究结果表明，椎间盘细胞衰老是PG基质稳态扰动和PG损失的重要驱动因素。
Aging greatly increases the risk for intervertebral disc degeneration (IDD) as a result of proteoglycan loss due to reduced synthesis and enhanced degradation of the disc matrix proteoglycan (PG). How disc matrix PG homeostasis becomes perturbed with age is not known. The goal of this study is to determine whether cellular senescence is a source of this perturbation. We demonstrated that disc cellular senescence is dramatically increased in the DNA repair-deficient Ercc1−/Δ mouse model of human progeria. In these accelerated aging mice, increased disc cellular senescence is closely associated with the rapid loss of disc PG. We also directly examine PG homeostasis in oxidative damage-induced senescent human cells using an in vitro cell culture model system. Senescence of human disc cells treated with hydrogen peroxide was confirmed by growth arrest, senescence-associated β-galactosidase activity, γH2AX foci, and acquisition of senescence-associated secretory phenotype. Senescent human disc cells also exhibited perturbed matrix PG homeostasis as evidenced by their decreased capacity to synthesize new matrix PG and enhanced degradation of aggrecan, a major matrix PG. of the disc. Our in vivo and in vitro findings altogether suggest that disc cellular senescence is an important driver of PG matrix homeostatic perturbation and PG loss.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
4
作者：
Rodier, Francis;Munoz, Denise P.;Campisi, Judith
通讯作者：
Campisi, Judith
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
5.3
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.
通讯作者：
Vo, Nam V.