Users Online: 135

Home Print this page Email this page Small font sizeDefault font sizeIncrease font size

Home | About us | Editorial board | Search | Ahead of print | Current issue | Archives | Submit article | Instructions | Subscribe | Contacts | Login 

   Table of Contents      
Year : 2021  |  Volume : 11  |  Issue : 3  |  Page : 206-210

Impact of Osteoprotegerin and RANKL on Non-ST-segment Elevation Myocardial Infarction

Department of Pharmaceutics, College of Pharmacy, Al-Nahrain University, Iraq

Date of Submission14-May-2021
Date of Decision19-May-2021
Date of Acceptance08-Jun-2021
Date of Web Publication28-Jul-2021

Correspondence Address:
Feryal Hashim Rada
Department of Pharmaceutics, College of Pharmacy, Al-Nahrain University
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijnpnd.ijnpnd_30_21

Rights and Permissions

Objective: Osteoprotogerin and receptor activator of nuclear factor kappa-B ligand (RANKL) formed an alliance that joining between bone remaking and vascular reforming. The aim of this study is to quantify the blood concentrations of osteoprotogerin and of RANKL in diabetic patients with myocardial infarction and to evaluate their relationship with other perilous factors in reference to healthy subjects. Methods: A total of 76 diabetic patients with myocardial infarction of non-ST-segment raising aged 50 to 60 years and their matched 60 healthy control aged 45 to 55 years were randomly selected from Al-yarmook Hospital and evaluated for inclusion in this case–control study. Blood levels of osteoprotogerin and RANKL were assessed using high-sensitive enzyme-linked immunosorbent assay. Results: The outcomes of this study elucidated increment in the blood concentrations of osteoprotogerin and RANKL in those patients. Apparently, significant positive correlation directed between osteoprotogerin level with age and onset of diabetes. Otherwise, lipid profile, and inflammatory markers exhibited no significant correlation with osteoprotogerin level. Conclusion: Upraised blood levels of osteoprotogerin and RANKL in diabetic patients with non-ST-segment raising myocardial infarction may be of a consequence of diabetic complication on vascular cell.

Keywords: Diabetes, non-ST-segment raising myocardial infarction, osteoprotogerin

How to cite this article:
Rada FH. Impact of Osteoprotegerin and RANKL on Non-ST-segment Elevation Myocardial Infarction. Int J Nutr Pharmacol Neurol Dis 2021;11:206-10

How to cite this URL:
Rada FH. Impact of Osteoprotegerin and RANKL on Non-ST-segment Elevation Myocardial Infarction. Int J Nutr Pharmacol Neurol Dis [serial online] 2021 [cited 2022 Dec 8];11:206-10. Available from:

   Introduction Top

Cardiovascular diseases are public diseases worldwide that related to many causes such as obesity which consequence to metabolic disorder,[1] diabetes which associated with inflammation and elevation of cytokines for instance C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α).[2],[3] Thereby changes in the penetrability of the vascular cells, and calcareous of the vascular arteries will occur.[4] TNF-α and IL-6 can decline the expression of peroxisome proliferator-activated receptors (PPARs) in adipocyte. On the other hand, the agonists of PPARγ can lessen the level of these cytokines in endothelial cells.[5]

Many studies asserted that there is an association either directly or indirectly between pathological changes in the vascular cells and blood levels of osteoprotegerin (OPG), a member of TNF superfamily, and its ligand which are either receptor activators of nuclear factor kappa-B ligand (RANKL) or TNF-related apoptosis-inducing ligand (TRAIL).[6]

The OPG, also named osteoclastogenesis inhibitory factor, is a protein made by osteoblast cell and acts as a bone protector by counteracting the over blood level of free RANKL through joining to it.[7] RANKL is a cytokine protein formed by ancestry osteoblast cell and activated lymphocyte cell. It has a transmembrane receptor (RANK) on dendritic cell and osteoclast cell. The existence of tie between RANKL and RANK causes increase in the multiplication and modification of the osteoclast cell escorting to bone resorb and for the dendritic cell escorting to inflammatory reaction.[8]

The OPG was also made by endothelial cell and discharged by many stimuli like inflammatory cytokines or hormone.[9] The OPG/RANKL/RANK axis and OPG/TRAIL axis separately made cross-talk between endothelial cell signaling pathways and osteocyte cell signaling pathways during osteogenesis and angiogenesis.[6] As OPG has a role in the physiology and pathology of the blood vessels, it has an atheroprotective and proatherogenic properties.[10] Clinically, OPG was known as a more unchangeable and dependable biological indicator than RANKL.[11]

The mission of this search is to quantify the blood levels of OPG and RANKL in diabetic patients with myocardial infarction of non-ST-segment raising (NST-MI) and to assess their association with other factors in contrast to healthy subjects.

   Methods Top

Study design and location

A total of 76 diabetic patients with NST-MI aged 50 to 60 years and their matched 60 healthy control aged 45 to 55 years were randomly selected from Al-yarmook Hospital in Iraq and evaluated for inclusion in this case–control study.

Ethical approval and patients’ selection

The procedure of this study followed the moralistic rules of World Medical Association of Helsinki Declaration for Ethical of Human Research and certified by the Institution’s Ethics Committee. Before enrolment, the participants received uttered and written details about the principle of this study and signed informed consent. Inclusion questionnaires ascertained information about the age, gender, history of diabetes and myocardial infarction, history of other diseases if present, current medication, and family history of health status. Omission criteria rejected the patients with inflammatory or infectious diseases, liver disease, kidney disease, or heart failure.

Data collection and laboratory measurements

At fasting, the blood samples are collected from each patient and centrifuged, and then the serum samples detached and kept at ‒20°C until analysis. Commercially available enzyme-linked immunosorbent assay (ELISA) kits used to quantify the levels of serum high-sensitive CRP (hs-CRP), OPG, and RANKL as to the employer’s guidelines and all the samples duplicated in examinations. Serum OPG quantify by kit (BioVendor) human OPG ELISA. Serum sRANKL (total) quantify by kit (BioVendor) human sRANKL (Total) ELISA technique.

Moreover, photometric–colorimetric assay kits used to quantify the serum levels of lipids, calcium, and albumin. Calcium level adjusted to the level of albumin by using this rule[12]:

Corrected calcium (mmoL/L) = Measured calcium (mmol/L) + 0.02 × [40 ‒ albumin (g/L)]

Statistical analyses

Numerous statistical evaluations implemented on Microsoft Excel and SPSS version 18 for windows. The normally distributed data organized as mean ± standard deviation with 95% confidence interval. The contrasts of incessant data tested using Student t test. Correlation analyses were assessed using Pearson correlation. All tests for statistical significance were two-tailed and P < 0.05 was opted as an endpoint for significance.

   Results Top

In this case–control study, all selected patients were fulfilled the criteria of inclusion. Healthy subjects and patients are well matched for age and gender distribution. The demographic and clinical data among the patients and the healthy control are summarized in [Table 1].
Table 1 Baseline characteristics and clinical data of the studied groups

Click here to view

As parallel to healthy control, the patients revealed statistically significant changes in lipid profile parameters that involved serum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), as noted in [Table 1]. Moreover, serum level of hs-CRP was elevated highly prominently in patients than in healthy subjects [Table 1] and it seemed to be 1.98-folded more than its level in healthy subjects [Figure 1].
Figure 1 Bar graph elucidated the number of the folded increased in serum levels of high-sensitive C-reactive protein (hs-CRP), osteoprotegerin (OPG), and receptor activator of nuclear factor-kappa-B ligand (RANKL) in those patients versus healthy levels.

Click here to view

Regarding the database of bone restructuring markers, serum OPG level was highly interestingly increase (P < 0.001) in diabetic patients as matched to healthy subjects. Likewise serum RANKL level was highly substantially increased (P < 0.001) in diabetic patients when paralleled to healthy subjects. On the other hand, undetectable differences observed in mean serum levels of calcium between studied groups, as noted in [Table 1]. As implied in [Figure 1], serum OPG level was 1.42-folded increased in patients more than its level in control subjects, whereas serum RANKL level was 1.64-folded increased in patients more than its level in control subjects.

The details of simple univariate linear regression models with OPG or RANKL as dependent variable and clinical or biochemical parameters as independent variables are summarized in [Table 2]. No significant correlation were existed between either OPG or RANKL with all independent variables except age and diabetes interval that were significantly correlated with serum OPG level, as illustrated in [Figure 2].
Table 2 Simple univariate linear regression summarizing associations between clinical parameters with osteoprotegerin and RANKL.

Click here to view
Figure 2 Percent variability of the osteoprotegerin level (bottom bars) and receptor activator of nuclear factor-kappa-B ligand (RANKL) level (top bars). *P < 0.05, significant correlation. HDL, high-density lipoprotein; hs-CRP, high-sensitive C-reactive protein; LDL, low-density lipoprotein.

Click here to view

Power analysis for minimum detectable changes in mean serum levels of OPG and RANKL in those patients as matched to control subjects is illustrated in [Figure 3]. Assuming in type I error (alpha), probability of false-positive results equal 0.05 and in type II error (beta), probability of false-negative results equal 0.2; therefore, power of analysis (1-B) equals 80%.
Figure 3 Power analysis for the minimum detectable change percentage (MDC%) within the mean levels of osteoprotegerin and receptor activator of nuclear factor-kappa-B ligand (RANKL).

Click here to view

   Discussion Top

The injury of the endothelial cells and thereafter the inflammatory reaction on the vascular cells caused many complications of different degrees that related to the cardiovascular diseases and triggered the release of cytokine proteins called OPG and RANKL.[13]

The laboratory and statistical results of this case–control study elucidated increase in the blood level of OPG in diabetic patients with NST-MI. Many studies declared that the blood level of OPG escalated with the existence of myocardial infarction,[14] and acute or unstable coronary syndrome.[11] On the contrary, other studies implied that the change in the blood level of OPG not allied with NST-MI or stable angina,[15] and it reduced in patients with stable cardiovascular diseases.[16]

Shetelig et al. verified that in hospitalized patients, the elevated blood level of OPG concomitant to acute phase of cardiovascular disease was due to intake of heparin injection. As OPG molecule has a domain for binding with heparin, the management with heparin injection for those hospitalized patients upraised the blood level of OPG, which gradually declined after many hours. The eventuality of the effect of ischemic injury on blood level of OPG was ruled out in this study.[17]

One of the menace factors that provoked atherosclerosis and arteriosclerosis by its micro- and macrovascular complication is diabetes mellitus. In concordance with other results that illustrated elevated blood level of OPG in diabetic patients with or without endothelial and vascular injury,[18],[19] high OPG level was stated in the current study for diabetic patients with NST-MI.

The RANKL is a cytokine protein that when tied with its receptor RANK on endothelial cell membrane triggered and stimulated factor of transcription called nuclear factor kappa-B guiding to many cascade of signaling gene transcription. Ultimately, it is enhanced endothelial cell dysfunction and boosted metalloproteinase, which minimized the durability of the vascular plaque. Therefore, the presence of circulatory free OPG was important to neutralize the excess free RANKL, and lessens the incidence of these complications.[20]

Concerning the blood level of RANKL in this study, statistical data reveal high blood level of RANKL in those patients with diabetes and NST-MI. This result was in accordance with other studies that reported high blood level of sRANKL in patients with cardiovascular disease.[21],[22] Contrariwise, a suppression in blood level of sRANKL was referred in patients have ST-segment raising MI as contrasted to the stable coronary disease.[13],[23]Seemingly, a positive correlation appeared in this study between OPG level with age and diabetes period. Moreover, lipid profile and inflammatory markers exhibited no significant correlation with OPG level. These outcomes were in line with the other studies.[24],[25] Likewise, the OPG level was not interrelated well with HDL-C,[26] whereas discrepant view inferred that HDL-C, not LDL-C, interrelated well with OPG.[27] Confirming with many studies,[16],[28] no interdepended found between RANKL level and other menace factors of cardiovascular diseases.

   Conclusion Top

The OPG and RANKL are cytokine proteins belong to the TNF superfamily and have cross-role between the events of bone cell, immune cell, and vascular cell. The provenance of higher blood levels of OPG and RANKL in diabetic patients with NST-MI may be related to the intricacies of diabetes on vascular cells.


The author acknowledges the Al-Nahrain University and Pharmacy College, Iraq for facilitating the requirements of this research.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Rada FH. Effect of lipid fractions levels with cardiovascular disease. Asian J Pharm Clin Res 2017;10:180-2.  Back to cited text no. 1
Rada FH. Assessment of pyrazino-pyrimidine compound and some inflammatory biomarkers in patients with type 2 diabetes. Int J Pharm Sci Res 2017;8:2691-5.  Back to cited text no. 2
Rada FH. Oxidative stress and some inflammatory biomarkers in patients with coronary heart disease. Eur J Pharm Med Res 2018;5:9-12.  Back to cited text no. 3
London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: Impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 2003;18:1731-40.  Back to cited text no. 4
Rada FH. Peroxisome proliferator-activated receptors family overview. Eur J Pharm Med Res 2019;6:167-70.  Back to cited text no. 5
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;20:705-24.  Back to cited text no. 6
Collin-Osdoby P. Regulation of vascular calcification by osteoclast regulatory factors RANK-L and osteoprotegerin. Circ Res 2004;95:1046-57.  Back to cited text no. 7
Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008;473:139-46.  Back to cited text no. 8
Cunha DA, Cito M, Carlsson PO et al. Thrombospondin1protects pancreatic beta-cells from lipotoxicity via the PERK-NRF2 pathway. Cell Death Differ 2016;23:1995-2006.  Back to cited text no. 9
Berezin A. Bone-related proteins as markers in vascular remodeling. In: Preedy VR, ed. Biomarkers in Bone Disease. Berlin: Springer 2016 p. 1-22.  Back to cited text no. 10
Canga A, Durakoğlugil ME, Erdoğan T et al. Elevated serum osteoprotegerin levels predict in-hospital major adverse cardiac events in patients with ST elevation myocardial infarction. J Cardiol 2012;60:355-60.  Back to cited text no. 11
Beckett G, Walker S, Rae P, Ashby P. Lecture notes clinical biochemistry. 8th ed. UK: Wiley-Blackwell 2010 p. 76.  Back to cited text no. 12
Venuraju SM, Yerramasu A, Corder R, Lahiri A. Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity. J Am Coll Cardiol 2010;55:2049-61.  Back to cited text no. 13
Lindberg S, Jensen JS, Hoffmann S et al. Osteoprotegerin levels change during STEMI and reflect cardiac function. Can J Cardiol 2014;30:1523-28.  Back to cited text no. 14
Aksu F, Özçelik F, Kunduracilar H 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. Turkey Kardiol Pol 2014;72:34-41.  Back to cited text no. 15
Mohammad Pour AH, Shamsara J, Nazemi S, Ghadirzadeh S, Shahsavand SH, Ramezani M. Evaluation of RANKL/OPG Serum Concentration Ratio as a NewBiomarker for Coronary Artery Calcification: A Pilot Study. Hindawi Publishing Corporation Thrombosis; 2012;2012:306263.  Back to cited text no. 16
Shetelig C, Limalanathan S, Eritsland J et al. Osteoprotegerin levels in ST-elevationmyocardial infarction: temporal profile and association with myocardial injury and left ventricular function. PLoS One 2017;12:e0173034.  Back to cited text no. 17
Gaudio A, Privitera F, Pulvirenti I, Canzonieri E, Rapisarda R, Fiore CE. Relationships between osteoprotegerin, receptor activator of the nuclear factor κB ligand and serum levels and carotid intima-media thickness in patients with type 2 diabetes mellitus. Panminerva Med 2014;56:221-5.  Back to cited text no. 18
Yu G, Ji X, Jin J, Bu S. Association of serum and vitreous concentrations of osteoprotegerin with diabetic retinopathy. Ann Clin Biochem 2015;52:232-6.  Back to cited text no. 19
Quercioli A, Mach F, Bertolotto M et al. Receptor activator of NF-kappa B ligand (RANKL) increases the release of neutrophil products associated with coronary vulnerability. Thromb Haemost 2012;107:124-39.  Back to cited text no. 20
Pesaro AE, Katz M, Liberman M et al. Circulating osteogenic proteins are associated with coronary artery calcification and increase after myocardial infarction. PLoS One 2018;13:e0202738.  Back to cited text no. 21
Malliga DE, Wagner D, Fahrleitner-Pammer A. The role of osteoprotegerin (OPG) receptor activator for nuclear factor kappaB ligand (RANKL) in cardiovascular pathology − a review. Wien Med Wochenschr 2011;161:565-70.  Back to cited text no. 22
Crisfaulli A, Micari A, Altavilla D et al. Serum levels of osteoprotegerin and RANKL in patients with ST elevation acute myocardial infarction. Clin Sci (Lond) 2005;109:389-95.  Back to cited text no. 23
Jono S, Otsuki S, Higashikuni Y et al. Serum osteoprotegerin levels and long-term prognosis in subjects with stable coronary artery disease. J Thromb Haemost 2010;8:1170-5.  Back to cited text no. 24
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;2016:1752854.  Back to cited text no. 25
Ayina Ayina CN, Boudou P, Fidaa I et al. Osteoprotegerin is not a determinant of metabolic syndrome in sub-Saharan Africans after age-adjustment. Ann Endocrinol (Paris) 2014;75:165-70.  Back to cited text no. 26
Bennett BJ, Scatena M, Kirk EA et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE−/− mice. Arterioscler Thromb Vasc Biol 2006;26:2117-4.  Back to cited text no. 27
Poornima IG, Mackey RH, Buhari AM, Cauley JA, Matthews KA, Kuller LH. Relationship between circulating serum osteoprotegerin and total receptor activator of nuclear kappa-B ligand levels, triglycerides, and coronary calcification in postmenopausal women. Menopause 2014;21:702-10.  Back to cited text no. 28


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
    Article Figures
    Article Tables

 Article Access Statistics
    PDF Downloaded124    
    Comments [Add]    

Recommend this journal