Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model
BackgroundFibrosis is a core pathological factor of ligamentum flavum hypertrophy (LFH) resulting in degenerative lumbar spinal stenosis. Autophagy plays a vital role in multi-organ fibrosis. However, autophagy has not been reported to be involved in the pathogenesis of LFH.MethodsThe LFH microarray...
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.973799/full |
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| author | Peng Li Cheng-shuo Fei Yan-lin Chen Ze-sen Chen Zhong-ming Lai Rui-qian Tan Yong-peng Yu Xin Xiang Jia-le Dong Jun-xiong Zhang Liang Wang Zhong-min Zhang |
| author_facet | Peng Li Cheng-shuo Fei Yan-lin Chen Ze-sen Chen Zhong-ming Lai Rui-qian Tan Yong-peng Yu Xin Xiang Jia-le Dong Jun-xiong Zhang Liang Wang Zhong-min Zhang |
| author_sort | Peng Li |
| collection | DOAJ |
| description | BackgroundFibrosis is a core pathological factor of ligamentum flavum hypertrophy (LFH) resulting in degenerative lumbar spinal stenosis. Autophagy plays a vital role in multi-organ fibrosis. However, autophagy has not been reported to be involved in the pathogenesis of LFH.MethodsThe LFH microarray data set GSE113212, derived from Gene Expression Omnibus, was analyzed to obtain differentially expressed genes (DEGs). Potential autophagy-related genes (ARGs) were obtained with the human autophagy regulator database. Functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were conducted to elucidate the underlying biological pathways of autophagy regulating LFH. Protein-protein interaction (PPI) network analyses was used to obtain hub ARGs. Using transmission electron microscopy, quantitative RT-PCR, Western blotting, and immunohistochemistry, we identified six hub ARGs in clinical specimens and bipedal standing (BS) mouse model.ResultsA total of 70 potential differentially expressed ARGs were screened, including 50 up-regulated and 20 down-regulated genes. According to GO enrichment and KEGG analyses, differentially expressed ARGs were mainly enriched in autophagy-related enrichment terms and signaling pathways related to autophagy. GSEA and GSVA results revealed the potential mechanisms by demonstrating the signaling pathways and biological processes closely related to LFH. Based on PPI network analysis, 14 hub ARGs were identified. Using transmission electron microscopy, we observed the autophagy process in LF tissues for the first time. Quantitative RT-PCR, Western blotting, and immunohistochemistry results indicated that the mRNA and protein expression levels of FN1, TGFβ1, NGF, and HMOX1 significantly higher both in human and mouse with LFH, while the mRNA and protein expression levels of CAT and SIRT1 were significantly decreased.ConclusionBased on bioinformatics analysis and further experimental validation in clinical specimens and the BS mouse model, six potential ARGs including FN1, TGFβ1, NGF, HMOX1, CAT, and SIRT1 were found to participate in the fibrosis process of LFH through autophagy and play an essential role in its molecular mechanism. These potential genes may serve as specific therapeutic molecular targets in the treatment of LFH. |
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| language | English |
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| publishDate | 2022-10-01 |
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| spelling | doaj.art-596457072e5246d3bd7aed452e53a9442022-12-22T02:25:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.973799973799Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice modelPeng Li0Cheng-shuo Fei1Yan-lin Chen2Ze-sen Chen3Zhong-ming Lai4Rui-qian Tan5Yong-peng Yu6Xin Xiang7Jia-le Dong8Jun-xiong Zhang9Liang Wang10Zhong-min Zhang11Division of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaDepartment of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangzhou, ChinaDivision of Spine Surgery, Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, ChinaBackgroundFibrosis is a core pathological factor of ligamentum flavum hypertrophy (LFH) resulting in degenerative lumbar spinal stenosis. Autophagy plays a vital role in multi-organ fibrosis. However, autophagy has not been reported to be involved in the pathogenesis of LFH.MethodsThe LFH microarray data set GSE113212, derived from Gene Expression Omnibus, was analyzed to obtain differentially expressed genes (DEGs). Potential autophagy-related genes (ARGs) were obtained with the human autophagy regulator database. Functional analyses including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Gene Set Enrichment Analysis (GSEA), and Gene Set Variation Analysis (GSVA) were conducted to elucidate the underlying biological pathways of autophagy regulating LFH. Protein-protein interaction (PPI) network analyses was used to obtain hub ARGs. Using transmission electron microscopy, quantitative RT-PCR, Western blotting, and immunohistochemistry, we identified six hub ARGs in clinical specimens and bipedal standing (BS) mouse model.ResultsA total of 70 potential differentially expressed ARGs were screened, including 50 up-regulated and 20 down-regulated genes. According to GO enrichment and KEGG analyses, differentially expressed ARGs were mainly enriched in autophagy-related enrichment terms and signaling pathways related to autophagy. GSEA and GSVA results revealed the potential mechanisms by demonstrating the signaling pathways and biological processes closely related to LFH. Based on PPI network analysis, 14 hub ARGs were identified. Using transmission electron microscopy, we observed the autophagy process in LF tissues for the first time. Quantitative RT-PCR, Western blotting, and immunohistochemistry results indicated that the mRNA and protein expression levels of FN1, TGFβ1, NGF, and HMOX1 significantly higher both in human and mouse with LFH, while the mRNA and protein expression levels of CAT and SIRT1 were significantly decreased.ConclusionBased on bioinformatics analysis and further experimental validation in clinical specimens and the BS mouse model, six potential ARGs including FN1, TGFβ1, NGF, HMOX1, CAT, and SIRT1 were found to participate in the fibrosis process of LFH through autophagy and play an essential role in its molecular mechanism. These potential genes may serve as specific therapeutic molecular targets in the treatment of LFH.https://www.frontiersin.org/articles/10.3389/fimmu.2022.973799/fullligamentum flavum hypertrophydegenerative lumbar spinal stenosisautophagyfibrosisbioinformatics analysisbipedal standing mouse |
| spellingShingle | Peng Li Cheng-shuo Fei Yan-lin Chen Ze-sen Chen Zhong-ming Lai Rui-qian Tan Yong-peng Yu Xin Xiang Jia-le Dong Jun-xiong Zhang Liang Wang Zhong-min Zhang Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model Frontiers in Immunology ligamentum flavum hypertrophy degenerative lumbar spinal stenosis autophagy fibrosis bioinformatics analysis bipedal standing mouse |
| title | Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model |
| title_full | Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model |
| title_fullStr | Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model |
| title_full_unstemmed | Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model |
| title_short | Revealing the novel autophagy-related genes for ligamentum flavum hypertrophy in patients and mice model |
| title_sort | revealing the novel autophagy related genes for ligamentum flavum hypertrophy in patients and mice model |
| topic | ligamentum flavum hypertrophy degenerative lumbar spinal stenosis autophagy fibrosis bioinformatics analysis bipedal standing mouse |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.973799/full |
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