Discovery and Validation of Immune Infiltration-related Genes for the Prognosis of Osteoporosis
-
Hualiang Xu
,
Furong Xu
,
Lihong Chen
,
Renchun Wu
,
Hongqing Ge
,
Aiguo Li
Abstract
Osteoporosis (OP), a widespread musculoskeletal disorder characterized by fragile bone fractures, has seen increasing attention regarding immune infiltration-related genes. These genes show significant predictive value in solid tumor prognosis and are now being explored for their roles in musculoskeletal diseases. This study identified osteoporosis-associated differentially expressed immune genes (OP-DEGs) by analyzing the overlap between OP-differentially expressed genes and immune genes.
To elucidate the functional implications of these genes, pathway enrichment analysis was conducted using Gene Ontology and KEGG databases. Additionally, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were employed to explore underlying mechanisms. A competitive endogenous RNA (ceRNA) network was constructed for critical OP-related immune genes, and immune infiltration analysis investigated micro-environmental characteristics. The diagnostic effectiveness of OP was evaluated using ROC curves. Finally, RT-PCR determined the expression levels of 15 key OP-related immune genes in OP and control groups.
The study identified 29 OP-DEGs. Extensive bioinformatics analysis pinpointed 15 key genes that could serve as potential biomarkers for OP diagnosis. RT-PCR results revealed significantly increased expression of VEGFA, HMOX1, RARA, CXCL10, hsa-miR-129-2-3p, OIP5-AS1, and HCG18 in the OP group compared to controls.
Our findings suggest that these immune-related genes may predict OP prognosis and offer new perspectives for early prevention and intervention strategies. The identification of specific immune genes involved in OP development highlights their potential as therapeutic targets for further investigation.
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24. Zhou Y, Gao Y, Xu C, Shen H, Tian Q, Deng HW. A novel approach for correction of crosstalk effects in pathway analysis and its application in osteoporosis research. Sci Rep Uk. 2018;8(1):668.
25. Li L, Yang M, Jin A. COL3A1, COL6A3, and SERPINH1 Are Related to Glucocorticoid Induced Osteoporosis Occurrence According to Integrated Bioinformatics Analysis. Med Sci Monitor. 2020;26:e925474.
26. Zhang X, Chen K, Chen X, Kourkoumelis N, Li G, Wang B, et al. Integrative Analysis of Genomics and Transcriptome Data to Identify Regulation Networks in Female Osteoporosis. Front Genet. 2020;11:600097.
27. Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, et al. NCBI GEO mining tens of millions of expression profiles database and tools update. Nucleic Acids Res. 2007;35(Database issue):D760 5.
28. Davis S, Meltzer PS. GEOquery a bridge between the Gene Expression Omnibus GEO and BioConductor. Bioinformatics. 2007;23(14):1846 7.
29. Bhattacharya S, Dunn P, Thomas CG, Smith B, Schaefer H, Chen J, et al. ImmPort, toward repurposing of open access immunological assay data for translational and clinical research. Sci Data. 2018;5:180015.
30. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
31. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology Tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25(1):25 9.
32. Kanehisa M, Goto S. KEGG kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27 30.
33. Yu G, Wang LG, Yan GR, He QY. DOSE An R Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics. 2015;31(4):608 9.
34. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis a knowledge based approach for interpreting genome wide expression profiles. P Natl Acad Sci Usa. 2005;102(43):15545 50.
35. Yu G, Wang LG, Han Y, He QY. clusterProfiler An R package for comparing biological themes among gene clusters. Omics. 2012;16(5):284 7.
36. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database MSigDB hallmark gene set collection. Cell Syst. 2015;1(6):417 25.
37. Hanzelmann S, Castelo R, Guinney J. GSVA gene set variation analysis for microarray and RNA seq data. Bmc Bioinformatics. 2013;14:7.
38. Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F, et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019;37(7):773 82.
39. Baldwin AJ. Series introduction the transcription factor NF kappa B and human disease. J Clin Invest. 2001;107(1):3 6.
40. Soifer HS, Rossi JJ, Saetrom P. MicroRNAs in disease and potential therapeutic applications. Mol Ther. 2007;15(12):2070 9.
41. Chang L, Zhou G, Soufan O, Xia J. miRNet 2.0 network based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res. 2020;48(W1):W244 51.
42. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498 504.
43. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, et al. pROC an open source package for R and S+ to analyze and compare ROC curves. Bmc Bioinformatics. 2011;12:77.
44. Che J, Yang J, Zhao B, Shang P. HO 1 A new potential therapeutic target to combat osteoporosis. Eur J Pharmacol. 2021;906:174219.
45. Liu X, Ji C, Xu L, Yu T, Dong C, Luo J. Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells. J Cell Biochem. 2018;119(7):5503 16.
46. Bak SU, Kim S, Hwang HJ, Yun JA, Kim WS, Won MH, et al. Heme oxygenase 1 HO 1 carbon monoxide CO axis suppresses RANKL induced osteoclastic differentiation by inhibiting redox sensitive NF kappa B activation. Bmb Rep. 2017;50(2):103 8.
47. Xiao L, Zhong M, Huang Y, Zhu J, Tang W, Li D, et al. Puerarin alleviates osteoporosis in the ovariectomy induced mice by suppressing osteoclastogenesis via inhibition of TRAF6 ROS dependent MAPK NF kappa B signaling pathways. Aging Albany NY. 2020;12(21):21706 29.
48. Charoenpanich A, Wall ME, Tucker CJ, Andrews DM, Lalush DS, Dirschl DR, et al. Cyclic tensile strain enhances osteogenesis and angiogenesis in mesenchymal stem cells from osteoporotic donors. Tissue Eng Pt A. 2014;20(1 2):67 78.
49. Yu T, You X, Zhou H, He W, Li Z, Li B, et al. MiR 16 5p regulates postmenopausal osteoporosis by directly targeting VEGFA. Aging Albany NY. 2020;12(10):9500 14.
50. Armas LA, Recker RR. Pathophysiology of osteoporosis new mechanistic insights. Endocrin Metab Clin. 2012;41(3):475 86.
51. Weitzmann MN. Bone and the Immune System. Toxicol Pathol. 2017;45(7):911 24.
52. Saxena Y, Routh S, Mukhopadhaya A. Immunoporosis Role of Innate Immune Cells in Osteoporosis. Front Immunol. 2021;12:687037.
53. Ng PY, Brigitte PRA, Pavlos NJ. Membrane trafficking in osteoclasts and implications for osteoporosis. Biochem Soc T. 2019;47(2):639 50.
54. Lee BS. Myosins in Osteoclast Formation and Function. Biomolecules. 2018;8(4)
55. Han G, Zuo J, Holliday LS. Specialized Roles for Actin in Osteoclasts Unanswered Questions and Therapeutic Opportunities. Biomolecules. 2019;9(1):17.
56. Ochiai S, Nishida Y, Higuchi Y, Morita D, Makida K, Seki T, et al. Short range UV LED irradiation in postmenopausal osteoporosis using ovariectomized mice. Sci Rep Uk. 2021;11(1):7875.
57. Morita D, Higuchi Y, Makida K, Seki T, Ikuta K, Ishiguro N, et al. Effects of ultraviolet irradiation with a LED device on bone metabolism associated with vitamin D deficiency in senescence accelerated mouse P6. Heliyon. 2020;6(2):e03499.
58. Garcia Alles LF, Giacometti G, Versluis C, Maveyraud L, de Paepe D, Guiard J, et al. Crystal structure of human CD1e reveals a groove suited for lipid exchange processes. P Natl Acad Sci Usa. 2011;108(32):13230 5.
59. During A. Osteoporosis A role for lipids. Biochimie. 2020;178:49 55.
60. Zhao H, Li Y, Zhang M, Qi L, Tang Y. Blood lipid levels in patients with osteopenia and osteoporosis A systematic review and meta analysis. J Bone Miner Metab. 2021;39(3):510 20.
61. Mocsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase A crucial player in diverse biological functions. Nat Rev Immunol. 2010;10(6):387 402.
62. Csete D, Simon E, Alatshan A, Aradi P, Dobo Nagy C, Jakus Z, et al. Hematopoietic or Osteoclast Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice. Front Immunol. 2019;10:937.
63. Jia Y, Tao Y, Lv C, Xia Y, Wei Z, Dai Y. Tetrandrine enhances the ubiquitination and degradation of Syk through an AhR c src c Cbl pathway and consequently inhibits osteoclastogenesis and bone destruction in arthritis. Cell Death Dis. 2019;10(2):38.
64. Xie G, Liu W, Lian Z, Xie D, Yuan G, Ye J, et al. Spleen tyrosine kinase SYK inhibitor PRT062607 protects against ovariectomy induced bone loss and breast cancer induced bone destruction. Biochem Pharmacol. 2021;188:114579.
2. Cheng X, Zhao K, Zha X, Du X, Li Y, Chen S, et al. Opportunistic Screening Using Low Dose CT and the Prevalence of Osteoporosis in China A Nationwide, Multicenter Study. J Bone Miner Res. 2021;36(3):427 35.
3. Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;393(10169):364 76.
4. Yang J, Tang Q, Che M, Shi J, Yang L, Zeng Y. Effect of bedside health education for elderly patients with fragility fracture by specialist physicians on the diagnosis and treatment of osteoporosis during hospitalization and the visiting rate to osteoporosis clinic after discharge in a high volume orthopedic hospital. Arch Osteoporos. 2023;18(1):133.
5. Matsumoto T, Endo I. RANKL as a target for the treatment of osteoporosis. J Bone Miner Metab. 2021;39(1):91 105.
6. Katoh M, Katoh M. Molecular genetics and targeted therapy of WNT related human diseases Review. Int J Mol Med. 2017;40(3):587 606.
7. De Martinis M, Sirufo MM, Ginaldi L. Osteoporosis Current and Emerging Therapies Targeted to Immunological Checkpoints. Curr Med Chem. 2020;27(37):6356 72.
8. Zhao W, Wang G, Zhou C, Zhao Q. The regulatory roles of long noncoding RNAs in osteoporosis. American Journal of Translational Research. 2020. 12(9): 5882 5907.
9. Ohnishi T, Ogawa Y, Suda K, Komatsu M, Harmon SM, Asukai M, et al. Molecular Targeted Therapy for the Bone Loss Secondary to Pyogenic Spondylodiscitis Using Medications for Osteoporosis A Literature Review. Int J Mol Sci. 2021;22(9)4453.
10. Ukon Y, Makino T, Kodama J, Tsukazaki H, Tateiwa D, Yoshikawa H, et al. Molecular Based Treatment Strategies for Osteoporosis A Literature Review. Int J Mol Sci. 2019;20(10):2557.
11. Eastell R, Szulc P. Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endo. 2017;5(11):908 23.
12. Ciuffi S, Donati S, Marini F, Palmini G, Luzi E, Brandi ML. Circulating MicroRNAs as Novel Biomarkers for Osteoporosis and Fragility Fracture Risk Is There a Use in Assessment Risk? Int J Mol Sci. 2020;21(18):6927.
13. Garnero P. The Utility of Biomarkers in Osteoporosis Management. Mol Diagn Ther. 2017. 21(4): 401 418.
14. Guder C, Gravius S, Burger C, Wirtz DC, Schildberg FA. Osteoimmunology A Current Update of the Interplay Between Bone and the Immune System. Front Immunol. 2020;11:58.
15. Fischer V, Haffner Luntzer M. Interaction between bone and immune cells Implications for postmenopausal osteoporosis. Semin Cell Dev Biol. 2022;123:14 21.
16. Ma M, Luo S, Chen X, Yuan F, Cai J, Lu L, et al. Immune system related differentially expressed genes, transcription factors and microRNAs in post menopausal females with osteopenia. Scand J Immunol. 2015;81(3):214 20.
17. Ma M, Luo S, Zhou W, Lu L, Cai J, Yuan F, et al. Bioinformatics analysis of gene expression profiles in B cells of postmenopausal osteoporosis patients. Taiwan J Obstet Gyne. 2017;56(2):165 70.
18. Hu B, Kong X, Li L, Dai F, Zhang Q, Shi R. Integrative Analyses of Genes Associated with Osteoporosis in CD16+ Monocyte. Front Endocrinol. 2020;11:581878.
19. Ma J, Lin X, Chen C, Li S, Zhang S, Chen Z, et al. Circulating miR 181c 5p and miR 497 5p Are Potential Biomarkers for Prognosis and Diagnosis of Osteoporosis. J Clin Endocr Metab. 2020;105(5):dgz300.
20. Wei Y, Ma H, Zhou H, Yin H, Yang J, Song Y, et al. miR 424 5p shuttled by bone marrow stem cells derived exosomes attenuates osteogenesis via regulating WIF1 mediated Wnt beta catenin axis. Aging Albany NY. 2021;13(13):17190 201.
21. Chen B, Yang W, Zhao H, Liu K, Deng A, Zhang G, et al. Abnormal expression of miR 135b 5p in bone tissue of patients with osteoporosis and its role and mechanism in osteoporosis progression. Exp Ther Med. 2020;19(2):1042 50.
22. Yao S, Guo Y, Dong SS, Hao RH, Chen XF, Chen YX, et al. Regulatory element based prediction identifies new susceptibility regulatory variants for osteoporosis. Hum Genet. 2017;136(8):963 74.
23. Yang TL, Shen H, Liu A, Dong SS, Zhang L, Deng FY, et al. A road map for understanding molecular and genetic determinants of osteoporosis. Nat Rev Endocrinol. 2020;16(2):91 103.
24. Zhou Y, Gao Y, Xu C, Shen H, Tian Q, Deng HW. A novel approach for correction of crosstalk effects in pathway analysis and its application in osteoporosis research. Sci Rep Uk. 2018;8(1):668.
25. Li L, Yang M, Jin A. COL3A1, COL6A3, and SERPINH1 Are Related to Glucocorticoid Induced Osteoporosis Occurrence According to Integrated Bioinformatics Analysis. Med Sci Monitor. 2020;26:e925474.
26. Zhang X, Chen K, Chen X, Kourkoumelis N, Li G, Wang B, et al. Integrative Analysis of Genomics and Transcriptome Data to Identify Regulation Networks in Female Osteoporosis. Front Genet. 2020;11:600097.
27. Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, et al. NCBI GEO mining tens of millions of expression profiles database and tools update. Nucleic Acids Res. 2007;35(Database issue):D760 5.
28. Davis S, Meltzer PS. GEOquery a bridge between the Gene Expression Omnibus GEO and BioConductor. Bioinformatics. 2007;23(14):1846 7.
29. Bhattacharya S, Dunn P, Thomas CG, Smith B, Schaefer H, Chen J, et al. ImmPort, toward repurposing of open access immunological assay data for translational and clinical research. Sci Data. 2018;5:180015.
30. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. Limma powers differential expression analyses for RNA sequencing and microarray studies. Nucleic Acids Res. 2015;43(7):e47.
31. Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology Tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25(1):25 9.
32. Kanehisa M, Goto S. KEGG kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27 30.
33. Yu G, Wang LG, Yan GR, He QY. DOSE An R Bioconductor package for disease ontology semantic and enrichment analysis. Bioinformatics. 2015;31(4):608 9.
34. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis a knowledge based approach for interpreting genome wide expression profiles. P Natl Acad Sci Usa. 2005;102(43):15545 50.
35. Yu G, Wang LG, Han Y, He QY. clusterProfiler An R package for comparing biological themes among gene clusters. Omics. 2012;16(5):284 7.
36. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database MSigDB hallmark gene set collection. Cell Syst. 2015;1(6):417 25.
37. Hanzelmann S, Castelo R, Guinney J. GSVA gene set variation analysis for microarray and RNA seq data. Bmc Bioinformatics. 2013;14:7.
38. Newman AM, Steen CB, Liu CL, Gentles AJ, Chaudhuri AA, Scherer F, et al. Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019;37(7):773 82.
39. Baldwin AJ. Series introduction the transcription factor NF kappa B and human disease. J Clin Invest. 2001;107(1):3 6.
40. Soifer HS, Rossi JJ, Saetrom P. MicroRNAs in disease and potential therapeutic applications. Mol Ther. 2007;15(12):2070 9.
41. Chang L, Zhou G, Soufan O, Xia J. miRNet 2.0 network based visual analytics for miRNA functional analysis and systems biology. Nucleic Acids Res. 2020;48(W1):W244 51.
42. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498 504.
43. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez JC, et al. pROC an open source package for R and S+ to analyze and compare ROC curves. Bmc Bioinformatics. 2011;12:77.
44. Che J, Yang J, Zhao B, Shang P. HO 1 A new potential therapeutic target to combat osteoporosis. Eur J Pharmacol. 2021;906:174219.
45. Liu X, Ji C, Xu L, Yu T, Dong C, Luo J. Hmox1 promotes osteogenic differentiation at the expense of reduced adipogenic differentiation induced by BMP9 in C3H10T1/2 cells. J Cell Biochem. 2018;119(7):5503 16.
46. Bak SU, Kim S, Hwang HJ, Yun JA, Kim WS, Won MH, et al. Heme oxygenase 1 HO 1 carbon monoxide CO axis suppresses RANKL induced osteoclastic differentiation by inhibiting redox sensitive NF kappa B activation. Bmb Rep. 2017;50(2):103 8.
47. Xiao L, Zhong M, Huang Y, Zhu J, Tang W, Li D, et al. Puerarin alleviates osteoporosis in the ovariectomy induced mice by suppressing osteoclastogenesis via inhibition of TRAF6 ROS dependent MAPK NF kappa B signaling pathways. Aging Albany NY. 2020;12(21):21706 29.
48. Charoenpanich A, Wall ME, Tucker CJ, Andrews DM, Lalush DS, Dirschl DR, et al. Cyclic tensile strain enhances osteogenesis and angiogenesis in mesenchymal stem cells from osteoporotic donors. Tissue Eng Pt A. 2014;20(1 2):67 78.
49. Yu T, You X, Zhou H, He W, Li Z, Li B, et al. MiR 16 5p regulates postmenopausal osteoporosis by directly targeting VEGFA. Aging Albany NY. 2020;12(10):9500 14.
50. Armas LA, Recker RR. Pathophysiology of osteoporosis new mechanistic insights. Endocrin Metab Clin. 2012;41(3):475 86.
51. Weitzmann MN. Bone and the Immune System. Toxicol Pathol. 2017;45(7):911 24.
52. Saxena Y, Routh S, Mukhopadhaya A. Immunoporosis Role of Innate Immune Cells in Osteoporosis. Front Immunol. 2021;12:687037.
53. Ng PY, Brigitte PRA, Pavlos NJ. Membrane trafficking in osteoclasts and implications for osteoporosis. Biochem Soc T. 2019;47(2):639 50.
54. Lee BS. Myosins in Osteoclast Formation and Function. Biomolecules. 2018;8(4)
55. Han G, Zuo J, Holliday LS. Specialized Roles for Actin in Osteoclasts Unanswered Questions and Therapeutic Opportunities. Biomolecules. 2019;9(1):17.
56. Ochiai S, Nishida Y, Higuchi Y, Morita D, Makida K, Seki T, et al. Short range UV LED irradiation in postmenopausal osteoporosis using ovariectomized mice. Sci Rep Uk. 2021;11(1):7875.
57. Morita D, Higuchi Y, Makida K, Seki T, Ikuta K, Ishiguro N, et al. Effects of ultraviolet irradiation with a LED device on bone metabolism associated with vitamin D deficiency in senescence accelerated mouse P6. Heliyon. 2020;6(2):e03499.
58. Garcia Alles LF, Giacometti G, Versluis C, Maveyraud L, de Paepe D, Guiard J, et al. Crystal structure of human CD1e reveals a groove suited for lipid exchange processes. P Natl Acad Sci Usa. 2011;108(32):13230 5.
59. During A. Osteoporosis A role for lipids. Biochimie. 2020;178:49 55.
60. Zhao H, Li Y, Zhang M, Qi L, Tang Y. Blood lipid levels in patients with osteopenia and osteoporosis A systematic review and meta analysis. J Bone Miner Metab. 2021;39(3):510 20.
61. Mocsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase A crucial player in diverse biological functions. Nat Rev Immunol. 2010;10(6):387 402.
62. Csete D, Simon E, Alatshan A, Aradi P, Dobo Nagy C, Jakus Z, et al. Hematopoietic or Osteoclast Specific Deletion of Syk Leads to Increased Bone Mass in Experimental Mice. Front Immunol. 2019;10:937.
63. Jia Y, Tao Y, Lv C, Xia Y, Wei Z, Dai Y. Tetrandrine enhances the ubiquitination and degradation of Syk through an AhR c src c Cbl pathway and consequently inhibits osteoclastogenesis and bone destruction in arthritis. Cell Death Dis. 2019;10(2):38.
64. Xie G, Liu W, Lian Z, Xie D, Yuan G, Ye J, et al. Spleen tyrosine kinase SYK inhibitor PRT062607 protects against ovariectomy induced bone loss and breast cancer induced bone destruction. Biochem Pharmacol. 2021;188:114579.
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1.
Xu H, Xu F, Chen L, Wu R, Ge H, Li A. Discovery and Validation of Immune Infiltration-related Genes for the Prognosis of Osteoporosis. Iran J Allergy Asthma Immunol. 2025;:1-25.
