Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.
Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.
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DOI：
10.1371/journal.pone.0024600
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bateman JF
中科院分区：
文献类型：
--
作者：
Cameron TL;Bell KM;Tatarczuch L;Mackie EJ;Rajpar MH;McDermott BT;Boot-Handford RP;Bateman JF
Schmid型干骺端软骨发育不良（MCDS）的特征是轻度身材矮小和生长板肥大区扩张，由胶原X突变引起。我们最近通过在肥大区表达错误折叠形式的胶原X（Schmid）或甲状腺球蛋白（Cog）来重现疾病表型，从而证明了ER应激在MCDS病理学中的核心重要性。在这里，我们的特点施密德和齿轮ER压力信号网络的转录分析的显微解剖的突变体和野生型肥大区。这两种模型显示出相似的未折叠蛋白反应（UPR），涉及典型ER应激传感器的激活及其下游靶点的上调，包括分子伴侣、折叠酶和ER相关降解机制。上调的还有新出现的UPR调节因子Wfs 1和Syvn 1，最近发现的UPR组分包括Armet和Creld 2，以及以前未参与ER应激的基因，如Steap 1和Fgf 21。尽管上调的Chop/Cebpb途径，细胞凋亡并没有增加突变肥大区。突变体生长板的超微结构分析显示ER应力和破坏整个突变体肥大区的软骨细胞成熟。通过分析突变肥大区中野生型生长板区基因特征的表达来定义这种破坏。肥大区基因上调和增殖区基因下调均在施密德肥大区被抑制，导致ER应激的施密德软骨细胞中增殖性软骨细胞样表达谱的持续存在。我们的研究结果提供了两个体内软骨细胞UPR基因网络的转录图谱，并定义了UPR激活对肥大期间经历ER应激的软骨细胞的适应、分化和存活的影响。因此，他们提供了重要的见解ER应激信号及其对软骨病理生理学的影响。
Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology.
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DOI：
10.1073/pnas.96.25.14523
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hubert, RS;Vivanco, I;Afar, DEH
通讯作者：
Afar, DEH
影响因子：
5.3
作者：
Di Jeso, B;Park, YN;Arvan, P
通讯作者：
Arvan, P
哺乳动物转录因子 ATF6 以跨膜蛋白的形式合成，并在内质网应激时通过蛋白水解激活
影响因子：
3.3
作者：
Haze, K;Yoshida, H;Mori, K
通讯作者：
Mori, K
DOI：
10.1016/s0934-8832(11)80075-2
发表时间：
1993-03-01
期刊：
MATRIX
影响因子：
--
作者：
APTE, SS;OLSEN, BR
通讯作者：
OLSEN, BR
影响因子：
3.7
作者：
Apostolou, Andria;Shen, Yuxian;Fang, Shengyun
通讯作者：
Fang, Shengyun