ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation.
ERK1 and ERK2 regulate chondrocyte terminal differentiation during endochondral bone formation.
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DOI：
10.1002/jbmr.2409
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发表时间：
2015-05
影响因子：
6.2
通讯作者：
Murakami, Shunichi
中科院分区：
文献类型：
--
作者：
Chen, Zhijun;Yue, Susan X.;Zhou, Guang;Greenfield, Edward M.;Murakami, Shunichi
关键词：
骨骺软骨中的软骨细胞在通过细胞凋亡被清除之前经历终末分化。为了研究ERK1和ERK2在软骨细胞终末分化中的作用，我们生成了Osx-Cre；ERK1 /−−;ERK2flox/flox小鼠（cKOosx），其中ERK1和ERK2在增生性软骨细胞中缺失。这些cKOosx小鼠出生时大小大体正常，但到3周龄时，长骨变短。组织学分析显示，生长板内增生性软骨细胞带明显扩大。原位杂交和实时荧光定量PCR分析显示，Mmp13和骨桥蛋白表达显著降低，提示软骨细胞终末分化受损。此外，野生型小鼠中表达仅限于增生性软骨细胞最后一层的转录因子Egr1和Egr2在这些cKOosx小鼠中也强烈下调。在RCS大鼠软骨肉瘤细胞系的瞬时转染实验中，Egr1、Egr2或MEK1的组成型活性突变体的表达增加了骨桥蛋白启动子的活性，而MEK1诱导的骨桥蛋白启动子的激活被Egr1和Egr2共同抑制因子Nab2的共同表达所抑制。这些结果表明，MEK1-ERK信号在一定程度上通过Egr1和Egr2激活骨桥蛋白启动子。最后，我们对cKOosx小鼠的组织学分析表明，骨髓中的内生软骨瘤样病变让人想起人的异软骨瘤病，这是一种由PTPN11突变引起的骨骼疾病。我们的观察结果表明，间软骨瘤的发展可能是由ERK MAPK信号的减少引起的。
Chondrocytes in the epiphyseal cartilage undergo terminal differentiation prior to their removal through apoptosis. To examine the role of ERK1 and ERK2 in chondrocyte terminal differentiation, we generated Osx-Cre; ERK1−/−; ERK2flox/flox mice (cKOosx), in which ERK1 and ERK2 were deleted in hypertrophic chondrocytes. These cKOosx mice were grossly normal in size at birth, but by 3 weeks of age exhibited shorter long bones. Histological analysis in these mice revealed that the zone of hypertrophic chondrocytes in the growth plate was markedly expanded. In situ hybridization and quantitative real-time PCR analyses demonstrated that Mmp13 and Osteopontin expression was significantly decreased, indicating impaired chondrocyte terminal differentiation. Moreover, Egr1 and Egr2, transcription factors whose expression is restricted to the last layers of hypertrophic chondrocytes in wild type mice, were also strongly downregulated in these cKOosx mice. In transient transfection experiments in the RCS rat chondrosarcoma cell line, the expression of Egr1, Egr2, or a constitutively active mutant of MEK1 increased the activity of an Osteopontin promoter, while the MEK1-induced activation of the Osteopontin promoter was inhibited by the co-expression of Nab2, an Egr1 and Egr2 co-repressor. These results suggest that MEK1-ERK signaling activates the Osteopontin promoter in part through Egr1 and Egr2. Finally, our histological analysis of cKOosx mice demonstrated enchondroma-like lesions in the bone marrow that are reminiscent of human metachondromatosis, a skeletal disorder caused by mutations in PTPN11. Our observations suggest that the development of enchondromas in metachondromatosis may be caused by reduced ERK MAPK signaling.
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影响因子：
4.5
作者：
Bowen ME;Ayturk UM;Kurek KC;Yang W;Warman ML
通讯作者：
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通讯作者：
Murakami, Shunichi
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通讯作者：
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