The Relationship between Serum and Gene Expression Levels of RANK, RANKL and Osteoprotegerin Inflammatory Pathway with Unstable Angina: A Case-control Study
-
Alireza Farrokhian
,
Mahtab Miraftab
,
Minoo Chenari
,
Hossein Akbari
,
Hassan Nikoueinejad
,
Effat Naimi
Abstract
Osteoprotegerin (OPG), receptor activator of nuclear factor-kappa B (RANK) and receptor activator of nuclear factor-kappa B ligand (RANKL), the members of the tumor necrosis factor (TNF) family, have multiple effects on bone metabolism, endocrine functions and, as an inflammatory pathway, in the immune system. This study tried to determine the association of the OPG/RANKL/RANK axis with the severity of unstable angina (UA) as an inflammatory condition.
Our study involved 50 patients with UA and 50 healthy people. Serum and peripheral blood mononuclear cells were isolated from all participants. Serum levels and gene expression of OPG, RANKL, and RANK in mononuclear cells were measured by enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (RT-PCR), respectively. For each patient with UA, the thrombolysis in myocardial infarction (TIMI) and the global registry of acute coronary events (GRACE) scores were determined to evaluate the severity of the disease. Then we analyzed the relation of OPG, RANKL, and RANK levels with TIMI and GRACE scores in patients with UA. Discriminate analysis was used to predict the combinational models of such factors on the prediction of UA.
Serum levels of OPG and RANKL (p<0.001) and gene expression of RANKL (p<0.001) were significantly more in patients than those in healthy ones. No relation was seen between the OPG/RANKL/RANK axis and the severity of UA according to TIMI and GRACE scores.
Our study shows that serum level, as well as gene expression of OPG/RANKL/RANK axis neither, predicts the occurrence of UA nor shows any relationship with its severity.
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7. Amin N, Boccardi V, Taghizadeh M, Jafarnejad S. Probiotics and bone disorders: the role of RANKL/RANK/OPG pathway. Aging Clin Exp Res. 2020;32(3):363-71.
8. Neale Weitzmann M. Bone and the Immune System. Toxicol Pathol. 2017;45(7):911-924.
9. Park-Min KH. Mechanisms involved in normal and pathological osteoclastogenesis. Cell Mol Life Sci. 2018;75(14):2519-28.
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11. Kiani AN, Aukrust P, Ueland T, Hollan I, Barr E, Magder LS, et al. Serum osteoprotegrin (OPG) in subclinical atherosclerosis in systemic lupus erythematosus. Lupus. 2017;26(8):865-70.
12. Irtiuga OB, Zhiduleva EV, Dubrovskaia OB, Moiseeva OM. Concentration of osteoprotegerin and RANKL in blood serum of patients with aortic stenosis. Kardiologiia. 2014;54(6):44-8.
13. Rochette L, Meloux A, Rigal E, Zeller M, Cottin Y, Vergely C. The Role of Osteoprotegerin and Its Ligands in Vascular Function. Int J Mol Sci. 2019;20(3):705.
14. Raaz-Schrauder D, Schrauder MG, Stumpf C, Lewczuk P, Kilian T, Dietel B, et al. Plasma levels of sRANKL and OPG are associated with atherogenic cytokines in patients with intermediate cardiovascular risk. Heart vessels. 2017;32(11):1304-13.
15. Bernardi S, Bossi F, Toffoli B, Fabris B. Roles and clinical applications of OPG and TRAIL as biomarkers in cardiovascular disease. BioMed Res Int. 2016;2016:1752864.
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17. Weiss-Sadan T, Gotsman I, Blum G. Cysteine proteases in atherosclerosis. FEBS J. 2017;284(10):1455-72.
18. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond). 2005;109(4):389-95.
19. Pesaro AE, Katz M, Liberman M, Pereira C, Mangueira CLP, de Carvalho AEZ, et al. Circulating osteogenic proteins are associated with coronary artery calcification and increase after myocardial infarction. PLoS One. 2018;13(8):e0202738.
20. Aksu F, Ozcelik F, Kunduracilar H, Barutçu A, Yel M, Umit EG, et al. The relation between the levels of osteoprotegerin and the degree of coronary artery disease in patients with acute coronary syndrome and stable angina pectoris. Kardiol Pol. 2014;72(1):34-41.
21. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin sci. 2005;109(4):389-95.
22. Poldervaart JM, Langedijk M, Backus BE, Dekker IMC, Six AJ, Doevendans PA, et al,. Comparison of the GRACE, HEART and TIMI score to predict major adverse cardiac events in chest pain patients at the emergency department. Int J Cardiol. 2017;227:656-61.
23. Numasawa Y, Kohsaka S, Miyata H, Kawamura A, Noma S, Suzuki M, et al. Use of thrombolysis in myocardial infarction risk score to predict bleeding complications in patients with unstable angina and non-ST elevation myocardial infarction undergoing percutaneous coronary intervention. Cardiovasc IntervTher. 2013;28(3):242-9.
24. Di Nisio C, Zizzari V.L, Zara S, Falconi M, Teti G, et al. RANK/RANKL/OPG Signaling Pathways in Necrotic Jaw Bone from Bisphosphonate-Treated Subjects. Eur J Histochem. 2015;59(1):2455.
25. Siasos G, Oikonomou E, Maniatis K, Georgiopoulos G, Kokkou E, Tsigkou V, et al. Prognostic significance of arterial stiffness and osteoprotegerin in patients with stable coronary artery disease. Eur j clin invest. 2018;48(3):e12890.
26. Demkova K, Kozarova M, Malachovska Z, Javorský M, Tkáč I. Osteoprotegerin concentration is associated with the presence and severity of peripheral arterial disease in type 2 diabetes mellitus. Vasa. 2018;47(2):131-5.
27. Göçer K, Aykan AÇ, Kılınç M, Göçer NS. Association of serum FGF-23, klotho, fetuin-A, osteopontin, osteoprotegerin and hs-CRP levels with coronary artery disease. Scand J Clin Lab Invest. 2020;1-5.
28. Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, et al. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS lett. 2002;521(1-3):180-4.
29. Musialik K, Szulinska M, Hen K, Skrypnik D, Bogdanski P. The relation between osteoprotegerin, inflammatory processes, and atherosclerosis in patients with metabolic syndrome. Eur Rev Med Pharmacol Sci. 2017;21(19):4379-85.
30. El Baz TZ, Khamis OA, El-Shehaby A, Chahine H, Alaa Al-Din Ahmed A, Alsawasany MA. Relationship between serum osteoprotegerin and vascular calcifications In hemodialysis patients. Egypt Heart J. 2017;69(2):149-155.
31. Ahmed S, Sobh R. Predictive Value of Osteoprotegerin for Detecting Coronary Artery Calcification in Type 2 Diabetes Mellitus Patients in Correlation with Extent of Calcification Detected by Multidetector Computed Tomography. Endocr Metab Immune DisordDrug Targets. 2019;19(6):845-51.
32. Çağlar S1, Çağlar A, Pilten S, Albay C, Beytemur O, Sarı H. Osteoprotegerin and 25-hydroxy vitamin D levels in patients with diabetic foot. Eklem Hastalik Cerrahisi. 2018;29(3):170-5.
33. Taylan A, Birlik M, Kenar G, Toprak B, Gundogdu B, Gurler O, et al. fibrosis, and vasculopathy in systemic Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis, skin sclerosis: a potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors. Mod Rheumatol. 2018;29(4):619-24.
34. Gamal RM, Gamal WM, Ghandour AM, Abozaid HS, Mohamed ME, Emad Y, et al. Study of the osteoprotegerin/receptor activator of nuclear factor-kB ligand system association with inflammation and atherosclerosis in systemic sclerosis. Immunol invest. 2018;47(3):241-50.
35. El-Asrar AM, Struyf S, Mohammad G, Gouwy M, Rytinx P, Siddiquei MM, et al. Osteoprotegerin is a new regulator of inflammation and angiogenesis in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2017;58(7):3189-201.
2. Li H, Sun K, Zhao R, Hu J, Hao Z, Wang F, et al. Inflammatory biomarkers of coronary heart disease. Front biosci. 2017;22:504-15.
3. Table S. Inflammation in atherosclerosis. Arch Cardiovasc Dis. 2016;109(12):708-715.
4. Ding R, Gao W, Ostrodci DH, He Z, Song Y, Ma L, et al. Effect of interleukin-2 level and genetic variants on coronary artery disease. Inflammation. 2013;36(6):1225-31.
5. Ji Q1, Zeng Q2, Huang Y3, Shi Y4, Lin Y4, Lu Z4, et al. Elevated plasma IL-37, IL-18, and IL-18BP concentrations in patients with acute coronary syndrome. Mediators inflamm. 2014;2014:165742.
6. Liu W, Zhang X. Receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin system in bone and other tissues. Mol Med Rep. 2015;11(5):3212-8.
7. Amin N, Boccardi V, Taghizadeh M, Jafarnejad S. Probiotics and bone disorders: the role of RANKL/RANK/OPG pathway. Aging Clin Exp Res. 2020;32(3):363-71.
8. Neale Weitzmann M. Bone and the Immune System. Toxicol Pathol. 2017;45(7):911-924.
9. Park-Min KH. Mechanisms involved in normal and pathological osteoclastogenesis. Cell Mol Life Sci. 2018;75(14):2519-28.
10. Kim JH1, Kim N1. Signaling Pathways in Osteoclast Differentiation. Chonnam Med J. 2016;52(1):12-7.
11. Kiani AN, Aukrust P, Ueland T, Hollan I, Barr E, Magder LS, et al. Serum osteoprotegrin (OPG) in subclinical atherosclerosis in systemic lupus erythematosus. Lupus. 2017;26(8):865-70.
12. Irtiuga OB, Zhiduleva EV, Dubrovskaia OB, Moiseeva OM. Concentration of osteoprotegerin and RANKL in blood serum of patients with aortic stenosis. Kardiologiia. 2014;54(6):44-8.
13. Rochette L, Meloux A, Rigal E, Zeller M, Cottin Y, Vergely C. The Role of Osteoprotegerin and Its Ligands in Vascular Function. Int J Mol Sci. 2019;20(3):705.
14. Raaz-Schrauder D, Schrauder MG, Stumpf C, Lewczuk P, Kilian T, Dietel B, et al. Plasma levels of sRANKL and OPG are associated with atherogenic cytokines in patients with intermediate cardiovascular risk. Heart vessels. 2017;32(11):1304-13.
15. Bernardi S, Bossi F, Toffoli B, Fabris B. Roles and clinical applications of OPG and TRAIL as biomarkers in cardiovascular disease. BioMed Res Int. 2016;2016:1752864.
16. Zhao H, Cao Y, Chen H, Xu W, Sun X, Pan X. The association between OPG rs3102735 gene polymorphism, microembolic signal and stroke severity in acute ischemic stroke patients. Gene. 2017;613:25-9.
17. Weiss-Sadan T, Gotsman I, Blum G. Cysteine proteases in atherosclerosis. FEBS J. 2017;284(10):1455-72.
18. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond). 2005;109(4):389-95.
19. Pesaro AE, Katz M, Liberman M, Pereira C, Mangueira CLP, de Carvalho AEZ, et al. Circulating osteogenic proteins are associated with coronary artery calcification and increase after myocardial infarction. PLoS One. 2018;13(8):e0202738.
20. Aksu F, Ozcelik F, Kunduracilar H, Barutçu A, Yel M, Umit EG, et al. The relation between the levels of osteoprotegerin and the degree of coronary artery disease in patients with acute coronary syndrome and stable angina pectoris. Kardiol Pol. 2014;72(1):34-41.
21. Crisafulli A, Micari A, Altavilla D, Saporito F, Sardella A, Passaniti M, et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin sci. 2005;109(4):389-95.
22. Poldervaart JM, Langedijk M, Backus BE, Dekker IMC, Six AJ, Doevendans PA, et al,. Comparison of the GRACE, HEART and TIMI score to predict major adverse cardiac events in chest pain patients at the emergency department. Int J Cardiol. 2017;227:656-61.
23. Numasawa Y, Kohsaka S, Miyata H, Kawamura A, Noma S, Suzuki M, et al. Use of thrombolysis in myocardial infarction risk score to predict bleeding complications in patients with unstable angina and non-ST elevation myocardial infarction undergoing percutaneous coronary intervention. Cardiovasc IntervTher. 2013;28(3):242-9.
24. Di Nisio C, Zizzari V.L, Zara S, Falconi M, Teti G, et al. RANK/RANKL/OPG Signaling Pathways in Necrotic Jaw Bone from Bisphosphonate-Treated Subjects. Eur J Histochem. 2015;59(1):2455.
25. Siasos G, Oikonomou E, Maniatis K, Georgiopoulos G, Kokkou E, Tsigkou V, et al. Prognostic significance of arterial stiffness and osteoprotegerin in patients with stable coronary artery disease. Eur j clin invest. 2018;48(3):e12890.
26. Demkova K, Kozarova M, Malachovska Z, Javorský M, Tkáč I. Osteoprotegerin concentration is associated with the presence and severity of peripheral arterial disease in type 2 diabetes mellitus. Vasa. 2018;47(2):131-5.
27. Göçer K, Aykan AÇ, Kılınç M, Göçer NS. Association of serum FGF-23, klotho, fetuin-A, osteopontin, osteoprotegerin and hs-CRP levels with coronary artery disease. Scand J Clin Lab Invest. 2020;1-5.
28. Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X, et al. PDGF induces osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS lett. 2002;521(1-3):180-4.
29. Musialik K, Szulinska M, Hen K, Skrypnik D, Bogdanski P. The relation between osteoprotegerin, inflammatory processes, and atherosclerosis in patients with metabolic syndrome. Eur Rev Med Pharmacol Sci. 2017;21(19):4379-85.
30. El Baz TZ, Khamis OA, El-Shehaby A, Chahine H, Alaa Al-Din Ahmed A, Alsawasany MA. Relationship between serum osteoprotegerin and vascular calcifications In hemodialysis patients. Egypt Heart J. 2017;69(2):149-155.
31. Ahmed S, Sobh R. Predictive Value of Osteoprotegerin for Detecting Coronary Artery Calcification in Type 2 Diabetes Mellitus Patients in Correlation with Extent of Calcification Detected by Multidetector Computed Tomography. Endocr Metab Immune DisordDrug Targets. 2019;19(6):845-51.
32. Çağlar S1, Çağlar A, Pilten S, Albay C, Beytemur O, Sarı H. Osteoprotegerin and 25-hydroxy vitamin D levels in patients with diabetic foot. Eklem Hastalik Cerrahisi. 2018;29(3):170-5.
33. Taylan A, Birlik M, Kenar G, Toprak B, Gundogdu B, Gurler O, et al. fibrosis, and vasculopathy in systemic Osteoprotegrin interacts with biomarkers and cytokines that have roles in osteoporosis, skin sclerosis: a potential multifaceted relationship between OPG/RANKL/TRAIL and Wnt inhibitors. Mod Rheumatol. 2018;29(4):619-24.
34. Gamal RM, Gamal WM, Ghandour AM, Abozaid HS, Mohamed ME, Emad Y, et al. Study of the osteoprotegerin/receptor activator of nuclear factor-kB ligand system association with inflammation and atherosclerosis in systemic sclerosis. Immunol invest. 2018;47(3):241-50.
35. El-Asrar AM, Struyf S, Mohammad G, Gouwy M, Rytinx P, Siddiquei MM, et al. Osteoprotegerin is a new regulator of inflammation and angiogenesis in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci. 2017;58(7):3189-201.
| Files | ||
| Issue | Vol 20 No 4 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i4.6957 | |
| Keywords | ||
| Osteoprotegerin Receptor activator of nuclear factor-kappa B RANK ligand Unstable angina | ||
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How to Cite
1.
Farrokhian A, Miraftab M, Chenari M, Akbari H, Nikoueinejad H, Naimi E. The Relationship between Serum and Gene Expression Levels of RANK, RANKL and Osteoprotegerin Inflammatory Pathway with Unstable Angina: A Case-control Study. Iran J Allergy Asthma Immunol. 2021;20(4):473-483.
