Identification of Drug Targets and Agents Associated with Ferroptosis-related Osteoporosis through Integrated Network Pharmacology and Molecular Docking Technology


Cite item

Full Text

Abstract

Background::Osteoporosis is a systemic bone disease characterized by progressive reduction of bone mineral density and degradation of trabecular bone microstructure. Iron metabolism plays an important role in bone; its imbalance leads to abnormal lipid oxidation in cells, hence ferroptosis. In osteoporosis, however, the exact mechanism of ferroptosis has not been fully elucidated.

Objective::The main objective of this project was to identify potential drug target proteins and agents for the treatment of ferroptosis-related osteoporosis.

Methods::In the current study, we investigated the differences in gene expression of bone marrow mesenchymal stem cells between osteoporosis patients and normal individuals using bioinformatics methods to obtain ferroptosis-related genes. We could predict their protein structure based on the artificial intelligence database of AlphaFold, and their target drugs and binding sites with the network pharmacology and molecular docking technology.

Results::We identified five genes that were highly associated with osteoporosis, such as TP53, EGFR, TGFB1, SOX2 and MAPK14, which, we believe, can be taken as the potential markers and targets for the diagnosis and treatment of osteoporosis. Furthermore, we observed that these five genes were highly targeted by resveratrol to exert a therapeutic effect on ferroptosis-related osteoporosis.

Conclusion::We examined the relationship between ferroptosis and osteoporosis based on bioinformatics and network pharmacology, presenting a promising direction to the pursuit of the exact molecular mechanism of osteoporosis so that a new target can be discovered for the treatment of osteoporosis.

About the authors

Kailun Huo

Postgraduate training base in Shanghai Gongli Hospital, Ningxia Medical University

Email: info@benthamscience.net

Yiqian Yang

Postgraduate training base in Shanghai Gongli Hospital, Ningxia Medical University

Email: info@benthamscience.net

Tieyi Yang

Department of Orthopedics, Shanghai Pudong New Area Gongli Hospital

Email: info@benthamscience.net

Weiwei Zhang

Department of Urology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine

Author for correspondence.
Email: info@benthamscience.net

Jin Shao

Department of Orthopedics, Shanghai Pudong New Area Gongli Hospital

Author for correspondence.
Email: info@benthamscience.net

References

  1. Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet 2019; 393(10169): 364-76. doi: 10.1016/S0140-6736(18)32112-3 PMID: 30696576
  2. Brown C. Staying strong. Nature 2017; 550(7674): S15-7. doi: 10.1038/550S15a PMID: 28976955
  3. Lane NE. Epidemiology, etiology, and diagnosis of osteoporosis. Am J Obstet Gynecol 2006; 194(S2): S3-S11. doi: 10.1016/j.ajog.2005.08.047 PMID: 16448873
  4. Yang Y, Lin Y, Wang M, et al. Targeting ferroptosis suppresses osteocyte glucolipotoxicity and alleviates diabetic osteoporosis. Bone Res 2022; 10(1): 26. doi: 10.1038/s41413-022-00198-w PMID: 35260560
  5. Liu P, Wang W, Li Z, et al. Ferroptosis: A new regulatory mechanism in osteoporosis. Oxid Med Cell Longev 2022; 2022: 1-10. doi: 10.1155/2022/2634431 PMID: 35082963
  6. Jiang X, Stockwell BR, Conrad M. Ferroptosis: Mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 2021; 22(4): 266-82. doi: 10.1038/s41580-020-00324-8 PMID: 33495651
  7. Hadian K, Stockwell BR. SnapShot: Ferroptosis. Cell 2020; 181(5): 1188-1188.e1. doi: 10.1016/j.cell.2020.04.039 PMID: 32470402
  8. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: The role of ferroptosis in cancer. Nat Rev Clin Oncol 2021; 18(5): 280-96. doi: 10.1038/s41571-020-00462-0 PMID: 33514910
  9. Chen X, Kang R, Kroemer G, Tang D. Ferroptosis in infection, inflammation, and immunity. J Exp Med 2021; 218(6): e20210518. doi: 10.1084/jem.20210518 PMID: 33978684
  10. Li N, Jiang W, Wang W, Xiong R, Wu X, Geng Q. Ferroptosis and its emerging roles in cardiovascular diseases. Pharmacol Res 2021; 166: 105466. doi: 10.1016/j.phrs.2021.105466 PMID: 33548489
  11. Xia Y, Zhang H, Wang H, et al. Identification and validation of ferroptosis key genes in bone mesenchymal stromal cells of primary osteoporosis based on bioinformatics analysis. Front Endocrinol 2022; 13: 980867. doi: 10.3389/fendo.2022.980867
  12. Luo C, Xu W, Tang X, et al. Canonical Wnt signaling works downstream of iron overload to prevent ferroptosis from damaging osteoblast differentiation. Free Radic Biol Med 2022; 188: 337-50. doi: 10.1016/j.freeradbiomed.2022.06.236 PMID: 35752374
  13. Barrett T, Wilhite SE, Ledoux P, et al. NCBI GEO: Archive for functional genomics data sets-update. Nucleic Acids Res 2012; 41(D1): D991-5. doi: 10.1093/nar/gks1193 PMID: 23193258
  14. Zhou N, Bao J. FerrDb: A manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. Database 2020; 2020: baaa021. doi: 10.1093/database/baaa021 PMID: 32219413
  15. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res 2021; 49(D1): D605-12. doi: 10.1093/nar/gkaa1074 PMID: 33237311
  16. Shannon P, Markiel A, Ozier O, et al. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13(11): 2498-504. doi: 10.1101/gr.1239303 PMID: 14597658
  17. Sherman BT, Hao M, Qiu J, et al. DAVID: A web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res 2022; 50(W1): W216-21. doi: 10.1093/nar/gkac194 PMID: 35325185
  18. 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. doi: 10.1093/nar/gkaa467 PMID: 32484539
  19. Yoo M, Shin J, Kim J, et al. DSigDB: Drug signatures database for gene set analysis. Bioinformatics 2015; 31(18): 3069-71. doi: 10.1093/bioinformatics/btv313 PMID: 25990557
  20. Kim S, Chen J, Cheng T, et al. PubChem 2023 update. Nucleic Acids Res 2023; 51(D1): D1373-80. doi: 10.1093/nar/gkac956 PMID: 36305812
  21. Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021; 596(7873): 583-9. doi: 10.1038/s41586-021-03819-2 PMID: 34265844
  22. Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoc 2016; 11(5): 905-19. doi: 10.1038/nprot.2016.051 PMID: 27077332
  23. Eberhardt J, Santos-Martins D, Tillack AF, Forli S. AutoDock vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model 2021; 61(8): 3891-8. doi: 10.1021/acs.jcim.1c00203 PMID: 34278794
  24. Zhao N, Zhang AS, Enns CA. Iron regulation by hepcidin. J Clin Invest 2013; 123(6): 2337-43. doi: 10.1172/JCI67225 PMID: 23722909
  25. Theil EC. Ferritin: The protein nanocage and iron biomineral in health and in disease. Inorg Chem 2013; 52(21): 12223-33. doi: 10.1021/ic400484n PMID: 24102308
  26. Yang WS, Stockwell BR. Ferroptosis: Death by lipid peroxidation. Trends Cell Biol 2016; 26(3): 165-76. doi: 10.1016/j.tcb.2015.10.014 PMID: 26653790
  27. Yang WS, SriRamaratnam R, Welsch ME, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156(1-2): 317-31. doi: 10.1016/j.cell.2013.12.010 PMID: 24439385
  28. Ponzetti M, Rucci N. Osteoblast differentiation and signaling: Established concepts and emerging topics. Int J Mol Sci 2021; 22(13): 6651. doi: 10.3390/ijms22136651 PMID: 34206294
  29. Tian Q, Qin B, Gu Y, et al. ROS-mediated necroptosis is involved in iron overload-induced osteoblastic cell death. Oxid Med Cell Longev 2020; 2020: 1-22. doi: 10.1155/2020/1295382 PMID: 33123307
  30. Bai X, Lu D, Liu A, et al. Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast. J Biol Chem 2005; 280(17): 17497-506. doi: 10.1074/jbc.M409332200 PMID: 15731115
  31. Ma J, Wang A, Zhang H, et al. Iron overload induced osteocytes apoptosis and led to bone loss in Hepcidin−/− mice through increasing sclerostin and RANKL/OPG. Bone 2022; 164: 116511. doi: 10.1016/j.bone.2022.116511 PMID: 35933095
  32. Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520(7545): 57-62. doi: 10.1038/nature14344 PMID: 25799988
  33. Zhen Y, Wang G, Zhu L, et al. P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol 2014; 229(10): 1475-83. doi: 10.1002/jcp.24589 PMID: 24615518
  34. Poursaitidis I, Wang X, Crighton T, et al. Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep 2017; 18(11): 2547-56. doi: 10.1016/j.celrep.2017.02.054 PMID: 28297659
  35. Chandra A, Lan S, Zhu J, Siclari VA, Qin L. Epidermal growth factor receptor (EGFR) signaling promotes proliferation and survival in osteoprogenitors by increasing early growth response 2 (EGR2) expression. J Biol Chem 2013; 288(28): 20488-98. doi: 10.1074/jbc.M112.447250 PMID: 23720781
  36. Kim S, Kang SW, Joo J, et al. Characterization of ferroptosis in kidney tubular cell death under diabetic conditions. Cell Death Dis 2021; 12(2): 160. doi: 10.1038/s41419-021-03452-x PMID: 33558472
  37. Kim DH, Kim WD, Kim SK, Moon DH, Lee SJ. TGF-β1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis 2020; 11(5): 406. doi: 10.1038/s41419-020-2618-6 PMID: 32471991
  38. Zhang P, Zhang H, Lin J, et al. Insulin impedes osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence via the TGF-β1 pathway. Aging 2020; 12(3): 2084-100. doi: 10.18632/aging.102723 PMID: 32017705
  39. Ashraf MI, Ebner M, Wallner C, et al. A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. Cell Commun Signal 2014; 12(1): 6. doi: 10.1186/1478-811X-12-6 PMID: 24423080
  40. Li L, Hao Y, Zhao Y, et al. Ferroptosis is associated with oxygen-glucose deprivation/reoxygenation-induced Sertoli cell death. Int J Mol Med 2018; 41(5): 3051-62. doi: 10.3892/ijmm.2018.3469 PMID: 29436589
  41. Caverzasio J, Higgins L, Ammann P. Prevention of trabecular bone loss induced by estrogen deficiency by a selective p38alpha inhibitor. J Bone Miner Res 2008; 23(9): 1389-97. doi: 10.1359/jbmr.080410 PMID: 18442314
  42. Wang X, Chen Y, Wang X, et al. Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res 2021; 81(20): 5217-29. doi: 10.1158/0008-5472.CAN-21-0567 PMID: 34385181
  43. Gan L, Leng Y, Min J, Luo XM, Wang F, Zhao J. Kaempferol promotes the osteogenesis in rBMSCs via mediation of SOX2/miR-124-3p/PI3K/Akt/mTOR axis. Eur J Pharmacol 2022; 927: 174954. doi: 10.1016/j.ejphar.2022.174954 PMID: 35421359
  44. Lu X, Kang N, Ling X, Pan M, Du W, Gao S. MiR-27a-3p promotes non-small cell lung cancer through SLC7A11-mediated-ferroptosis. Front Oncol 2021; 11: 759346. doi: 10.3389/fonc.2021.759346 PMID: 34722314
  45. Ren LR, Yao RB, Wang SY, Gong XD, Xu JT, Yang KS. MiR-27a-3p promotes the osteogenic differentiation by activating CRY2/ERK1/2 axis. Mol Med 2021; 27(1): 43. doi: 10.1186/s10020-021-00303-5 PMID: 33902432
  46. Chen X, Song X, Zhao X, et al. Insights into the anti-inflammatory and antiviral mechanisms of resveratrol. Mediators Inflamm 2022; 2022: 1-11. doi: 10.1155/2022/7138756 PMID: 35990040
  47. Liu J, Zhang M, Qin C, et al. Resveratrol attenuate myocardial injury by inhibiting ferroptosis via inducing KAT5/GPX4 in myocardial infarction. Front Pharmacol 2022; 13: 906073. doi: 10.3389/fphar.2022.906073 PMID: 35685642
  48. Pearson KJ, Baur JA, Lewis KN, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8(2): 157-68. doi: 10.1016/j.cmet.2008.06.011 PMID: 18599363
  49. Xiu X, Puskar NL, Shanata JAP, Lester HA, Dougherty DA. Nicotine binding to brain receptors requires a strong cation-π interaction. Nature 2009; 458(7237): 534-7. doi: 10.1038/nature07768 PMID: 19252481
  50. Zhu T, Shi L, Yu C, et al. Ferroptosis promotes photodynamic therapy: Supramolecular photosensitizer-inducer nanodrug for enhanced cancer treatment. Theranostics 2019; 9(11): 3293-307. doi: 10.7150/thno.32867 PMID: 31244955
  51. Das S, Lin HS, Ho PC, Ng KY. The impact of aqueous solubility and dose on the pharmacokinetic profiles of resveratrol. Pharm Res 2008; 25(11): 2593-600. doi: 10.1007/s11095-008-9677-1 PMID: 18629618
  52. Kosuru R, Rai U, Prakash S, Singh A, Singh S. Promising therapeutic potential of pterostilbene and its mechanistic insight based on preclinical evidence. Eur J Pharmacol 2016; 789: 229-43. doi: 10.1016/j.ejphar.2016.07.046 PMID: 27475678
  53. Lin HS, Yue BD, Ho PC. Determination of pterostilbene in rat plasma by a simple HPLC-UV method and its application in pre- clinical pharmacokinetic study. Biomed Chromatogr 2009; 23(12): 1308-15. doi: 10.1002/bmc.1254 PMID: 19488981
  54. Larrosa M, Barberán TFA, Espín JC. The grape and wine polyphenol piceatannol is a potent inducer of apoptosis in human SK-Mel-28 melanoma cells. Eur J Nutr 2004; 43(5): 275-84. doi: 10.1007/s00394-004-0471-5 PMID: 15309446
  55. Chen W, Yeo SCM, Elhennawy MGAA, Xiang X, Lin HS. Determination of naturally occurring resveratrol analog trans-4,4′-dihydroxystilbene in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study. Anal Bioanal Chem 2015; 407(19): 5793-801. doi: 10.1007/s00216-015-8762-7 PMID: 25998136
  56. Li XZ, Wei X, Zhang CJ, et al. Hypohalous acid-mediated halogenation of resveratrol and its role in antioxidant and antimicrobial activities. Food Chem 2012; 135(3): 1239-44. doi: 10.1016/j.foodchem.2012.05.043 PMID: 22953849
  57. Lee EJ, Min HY, Joo Park H, et al. G2/M cell cycle arrest and induction of apoptosis by a stilbenoid, 3,4,5-trimethoxy-4′-bromo- cis-stilbene, in human lung cancer cells. Life Sci 2004; 75(23): 2829-39. doi: 10.1016/j.lfs.2004.07.002 PMID: 15464834

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers