Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival.
Inhibition of apoptosis signal-regulating kinase 1 enhances endochondral bone formation by increasing chondrocyte survival.
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DOI：
10.1038/cddis.2014.480
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发表时间：
2014-11-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
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软骨内成骨是软骨细胞分化、肥大、死亡和骨替代的结果。这一过程的谨慎时机和进展对正常的骨骼生长和发育以及骨折修复是重要的。凋亡信号调节激酶1 （Apoptosis Signal-Regulating Kinase 1, ASK1）是一种丝裂原活化蛋白激酶（MAPK），可被活性氧和其他细胞应激事件激活。ASK1的激活启动了一个已知的信号级联，可以调节多种细胞事件，包括细胞因子和生长因子信号传导、细胞周期调节、细胞分化、肥大、存活和凋亡。ASK1在增生性软骨细胞中高度表达，但ASK1在骨组织中的作用尚未被研究。在此，我们报告ASK1基因敲除（KO）小鼠显示正常生长板形态的改变，包括较短的增殖区和延长的肥厚区。生长板动力学的这些变化导致长骨矿化加速和小梁骨形成增加，这可归因于终分化软骨细胞对细胞死亡的抵抗力增加。有趣的是，在正常细胞培养条件下，来自ASK1 KO小鼠的小鼠胚胎成纤维细胞（mef）与野生型（WT） mef相比，在MAPK信号传导或成骨或软骨分化方面均无差异。然而，当与应激激活剂、H2O2或staurosporine一起培养时，KO细胞表现出更高的存活率，与死亡信号通路相关的蛋白质激活减少，终端分化标志物减少。此外，在异位骨化模型中，用ASK1抑制剂NQDI-1处理的WT小鼠和ASK1 KO小鼠软骨内骨形成均增加。这些发现强调了ASK1在调节软骨内骨形成中的作用。抑制ASK1具有通过增强软骨细胞存活和减缓肥大来治疗骨折或减缓骨关节炎进展的临床潜力。
Endochondral ossification is the result of chondrocyte differentiation, hypertrophy, death and replacement by bone. The careful timing and progression of this process is important for normal skeletal bone growth and development, as well as fracture repair. Apoptosis Signal-Regulating Kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK), which is activated by reactive oxygen species and other cellular stress events. Activation of ASK1 initiates a signaling cascade known to regulate diverse cellular events including cytokine and growth factor signaling, cell cycle regulation, cellular differentiation, hypertrophy, survival and apoptosis. ASK1 is highly expressed in hypertrophic chondrocytes, but the role of ASK1 in skeletal tissues has not been investigated. Herein, we report that ASK1 knockout (KO) mice display alterations in normal growth plate morphology, which include a shorter proliferative zone and a lengthened hypertrophic zone. These changes in growth plate dynamics result in accelerated long bone mineralization and an increased formation of trabecular bone, which can be attributed to an increased resistance of terminally differentiated chondrocytes to undergo cell death. Interestingly, under normal cell culture conditions, mouse embryonic fibroblasts (MEFs) derived from ASK1 KO mice show no differences in either MAPK signaling or osteogenic or chondrogenic differentiation when compared with wild-type (WT) MEFs. However, when cultured with stress activators, H2O2 or staurosporine, the KO cells show enhanced survival, an associated decrease in the activation of proteins involved in death signaling pathways and a reduction in markers of terminal differentiation. Furthermore, in both WT mice treated with the ASK1 inhibitor, NQDI-1, and ASK1 KO mice endochondral bone formation was increased in an ectopic ossification model. These findings highlight a previously unrealized role for ASK1 in regulating endochondral bone formation. Inhibition of ASK1 has clinical potential to treat fractures or to slow osteoarthritic progression by enhancing chondrocyte survival and slowing hypertrophy.
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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：
7.8
作者：
Jilka RL;Almeida M;Ambrogini E;Han L;Roberson PK;Weinstein RS;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
10.5
作者：
Nishitoh, H;Matsuzawa, A;Ichijo, H
通讯作者：
Ichijo, H
影响因子：
--
作者：
KLEMENT, BJ;SPOONER, BS
通讯作者：
SPOONER, BS
影响因子：
15.9
作者：
Miura, M;Chen, XD;Shi, ST
通讯作者：
Shi, ST