文章摘要
王欢博,贺婷,郑超,等.Indian Hedgehog信号通路在软骨细胞成熟及转分化过程中的调控作用.骨科,2021,12(6): 485-492.
Indian Hedgehog信号通路在软骨细胞成熟及转分化过程中的调控作用
Effect of Indian Hedgehog Signaling on Maturation and Transdifferentiation of Chondrocytes
投稿时间:2021-08-27  
DOI:10.3969/j.issn.1674-8573.2021.06.001
中文关键词: Indian Hedgehog信号通路  软骨内成骨  肥大软骨细胞  转分化
英文关键词: Indian Hedgehog signaling  Endochondral ossification  Hypertrophic chondrocyte  Transdifferentiation
基金项目:国家自然科学基金资助项目(81772377、82002261);陕西省创新能力支撑项目计划(S2020-ZC-0036)
作者单位E-mail
王欢博 空军军医大学附属西京医院骨科西安 710032  
贺婷 西北工业大学医学研究院西安 710072  
郑超 空军军医大学附属西京医院骨科西安 710032  
卢玮光 空军军医大学附属西京医院骨科西安 710032  
范静 空军军医大学附属西京医院骨科西安 710032  
颉强 西安交通大学医学院附属红会医院儿童骨病医院西安 710054  
杨柳 空军军医大学附属西京医院骨科西安 710032西北工业大学医学研究院西安 710072 yangliu@fmmu.edu.cn 
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中文摘要:
      目的 探究Indian Hedgehog(IHH)信号通路对软骨内成骨过程中软骨细胞成熟以及转分化的影响。方法 取10日龄野生型小鼠的胫骨组织,采用原位杂交和免疫组织化学染色检测生长板区域IHH信号通路相关分子IhhPtch1Gli1的表达水平。构建肥大软骨细胞特异性Ihh基因敲除小鼠(Col10a1Cre/+; Ihhnull/C),并采用影像学检查和阿利新蓝染色评估该小鼠的骨骼发育状况。构建肥大软骨细胞IHH信号通路持续激活小鼠(Col10a1Cre/+; R26SmoM2/M2Col10a1Cre/+; Ptch1LacZ/C),采用HE染色、原位杂交和TUNEL染色分别对受精15.5天胎鼠胫骨组织形态结构、Ihh(肥大软骨细胞分子标志物)和Col1a1(成骨细胞分子标志物)以及肥大软骨细胞凋亡水平进行检测;另外应用HE染色对10日龄小鼠的胫骨组织进行组织学分析。结果 肥大软骨细胞合成分泌IHH,但不表达Ptch1Gli1。抑制肥大软骨细胞合成IHH蛋白会导致出生后小鼠出现侏儒症;X线检查结果显示小鼠出现严重的骨骼发育不良,包括胸廓狭小、球形头骨以及椎骨发育异常等表现。持续启动IHH信号通路时,胚胎早期软骨细胞成熟分化过程虽未见异常,但是出生后小鼠的骨小梁、骨内膜以及皮质骨等结构均出现一定的异常表现。结论 IHH信号通路虽然不参与肥大软骨细胞的终末分化过程,但在软骨细胞转分化的过程中起到了重要的调控作用。
英文摘要:
      Objective To explore the effect of Indian Hedgehog (IHH) signaling on the maturation and transdifferentiation of chondrocytes in endochondral ossification. Methods We utilized in situ hybridization and immunohistochemistry to detect the expression of IHH signaling-related molecules (Ihh, Ptch1 and Gli1) on tibia sections of wild type mice at P10. Next, we ablated Ihh gene in hypertrophic chondrocytes to establish Col10a1Cre/+; Ihhnull/C mice. We evaluated the skeletal development of the mice via X-ray and Alcian blue staining. Finally, we also established Col10a1Cre/+; R26SmoM2/M2 mice and Col10a1Cre/+; Ptch1LacZ/C mice in which IHH signaling was consistently activated in hypertrophic chondrocytes. We used HE staining, in situ hybridization and TUNEL assay to detect bone structure, the molecular markers of hypertrophic chondrocytes and osteoblasts and the situation of cell apoptosis on tibia sections of mice at E15.5. In addition, histological analysis on the tibias of these mice were performed by HE staining. Results Hypertrophic chondrocytes synthesized and secreted IHH, but they did not express Ptch1 and Gli1. Inhibiting the synthesis of IHH in hypertrophic chondrocytes led to dwarfism at postnatal stage. X-ray analysis revealed abnormal skeletal development, including small rib cage, spherical skull and abnormal vertebra. Although constitutive activation of IHH signaling did not impinge on the maturation of chondrocytes in early embryo, there were abnormal manifestations in primary spongiosa, endosteum and cortical bone at postnatal stage. Conclusion IHH signaling pathway does not regulate the terminal differentiation of hypertrophic chondrocytes, but it plays a critical role in cartilage-to-bone transition.
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