Sustained Akt signaling in articular chondrocytes causes osteoarthritis via oxidative stress-induced senescence in mice
Sustained Akt signaling in articular chondrocytes causes osteoarthritis via oxidative stress-induced senescence in mice
复制标题
关节软骨细胞中持续的 Akt 信号传导通过氧化应激诱导小鼠衰老导致骨关节炎
DOI：
10.1038/s41413-019-0062-y
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发表时间：
2019-08
期刊：
影响因子：
12.7
通讯作者：
Yang Xiao
中科院分区：
文献类型：
--
作者：
Xie Jing;Lin Jingting;Wei Min;Teng Yan;He Qi;Yang Guan;Yang Xiao
骨关节炎（OA）是一种与年龄相关的疾病，与软骨细胞衰老密切相关。破坏性的PTEN/Akt信号传导和软骨细胞衰老之间的因果关系和潜在机制尚不清楚。在这项研究中，我们发现激活Akt信号在人类OA软骨以及在小鼠OA模型与手术不稳定的内侧半月板。通过模拟由Col 2a 1-Cre或Col 2a 1-Cre~（ERT 2）驱动的PTEN缺陷在关节软骨细胞中持续的Akt信号传导的遗传小鼠模型发生OA，而限制Akt信号传导逆转了PTEN缺陷小鼠的OA表型。从机制上讲，Akt信号转导的长期激活引起活性氧的积累，并触发软骨细胞衰老以及衰老相关的分泌表型，而长期给予抗氧化剂N-乙酰半胱氨酸抑制软骨细胞衰老，减轻PTEN缺陷小鼠OA进展。因此，通过PTEN抑制Akt信号传导是维持关节软骨所必需的。关节软骨细胞中Akt信号传导中断触发氧化应激诱导的软骨细胞衰老并导致OA。
Osteoarthritis (OA) is an age-related disorder that is strongly associated with chondrocyte senescence. The causal link between disruptive PTEN/Akt signaling and chondrocyte senescence and the underlying mechanism are unclear. In this study, we found activated Akt signaling in human OA cartilage as well as in a mouse OA model with surgical destabilization of the medial meniscus. Genetic mouse models mimicking sustained Akt signaling in articular chondrocytes via PTEN deficiency driven by either Col2a1-Cre or Col2a1-Cre~(ERT2) developed OA, whereas restriction of Akt signaling reversed the OA phenotypes in PTEN-deficient mice. Mechanistically, prolonged activation of Akt signaling caused an accumulation of reactive oxygen species and triggered chondrocyte senescence as well as a senescence-associated secretory phenotype, whereas chronic administration of the antioxidant N-acetylcysteine suppressed chondrocyte senescence and mitigated OA progression in PTEN-deficient mice. Therefore, inhibition of Akt signaling by PTEN is required for the maintenance of articular cartilage. Disrupted Akt signaling in articular chondrocytes triggers oxidative stress-induced chondrocyte senescence and causes OA.
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影响因子：
13.3
作者：
Jackson, Miriam T.;Moradi, Babak;Little, Christopher B.
通讯作者：
Little, Christopher B.
DOI：
10.1007/978-3-030-39982-5_7
发表时间：
2020
期刊：
Pain Management for Clinicians
影响因子：
--
作者：
Nilofar Syed;Una E. Makris
通讯作者：
Nilofar Syed;Una E. Makris
DOI：
10.1084/jem.20062525
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Morita K;Miyamoto T;Fujita N;Kubota Y;Ito K;Takubo K;Miyamoto K;Ninomiya K;Suzuki T;Iwasaki R;Yagi M;Takaishi H;Toyama Y;Suda T
通讯作者：
Suda T
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
影响因子：
64.5
作者：
Manning BD;Toker A
通讯作者：
Toker A