As a novel osteogenic protein, the osteoclast-associated receptor (OSCAR) plays an important role in the process of osteoclastogenesis (1). OSCAR can be divided into soluble and membranous forms (2). Previous studies have found there to be a correlation between OSCAR and osteoarticular disease or osteoporosis (3-5). In recent years, it was found that OSCAR was involved in the inflammatory response and the cell activation in the process of arteriosclerosis, acting as an immunological mediator and a regulator of the osteoclast differentiation (6). Moreover, OSCAR was also identified as playing an important role for both vascular inflammation and/or plaque vulnerability during atherosclerosis (7). However, the correlations between sOSCAR and ACS are largely unknown. The aim of this work is to evaluate the association between sOSCAR and ACS.
A total of 41 ACS patients, of which 23 were male and 18 were female, admitted to the Second Affiliated Hospital of Nantong University from the dates of March 2017 to June 2017, were enrolled in this study. The clinical features of all the patients were confirmed using the diagnostic criteria set for ACS (8,9). Additionally the other 33 non-ACS patients were enrolled as a control, which included patients with stable angina and normal coronary angiography result. The age, gender, hypertension status, hyperlipemia status, diabetes status and smoking history of the patients were recorded after admission. Moreover, fasting venous blood samples were collected on the next morning after their admission, and the levels of hypersensitive C-reactive protein (hs-CRP), cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured. Patients were excluded from the study if they had any of the following: acute infectious disease, acute infection, connective tissue disease, malignant tumor, hepatorenal dysfunction, history of hematopathy, skeletal and joint disorders, major surgery, congenital heart disease, valvular heart disease and/or cardiomyopathy.
Four ml of fasting peripheral whole blood was fetched and put into a centrifuge, and set to 2,500 rpm for 10 min. The supernatant was taken and preserved in a −80 °C refrigerator until its application. The human soluble OSCAR ELISA kit was purchased from BioTSZ (HG30932, 96 Tests, CITY, STATE) with a detection range of 6–650 pg/mL.
The measurement data were presented as means ± the standard deviation, while those conforming to a skewed distribution were expressed as M (P25–P75). Afterwards, the enumeration data were then presented as a percentage or frequency. Measurement data between the two groups were then compared using an independent-sample t-test or the Mann-Whitney U test. While the enumeration data were compared using the chi-square test. Multivariable logistic regression analyses were used to identify the independent risk factors for the presence of ACS. Data were analyzed using the SPSS 17.0 (SPSS Inc., Chicago, Illinois) and the Med-Calc (version 11.2.1; MedCalc, Mariakerke, Belgium) software. P<0.05 was deemed statistically significant.
The comparative results of the baseline data from the two groups were as follows: sOSCAR level and LVEF in ACS group were lower than those in the non-ACS group (P<0.05), whereas hs-CRP and NT-proBNP levels in the ACS group were higher than those in the non-ACS group (P<0.05) (Table 1).
The area under the receiver–operating characteristic curve for sOSCAR was 0.691 for predicting ACS, with the cut-off value of 110.87 pg/mL, a 95% confidence interval of 0.573–0.793, a sensitivity of 65.85% and a specificity of 69.70% (P<0.05) (Figure 1).
Moreover, a multivariate regression analysis indicated that sOSCAR (OR: 0.174, 95% CI: 0.047–0.638, P=0.008) and NT-proBNP (OR: 6.636, 95% CI: 1.821–25.193, P=0.004) were independently associated with the presence of ACS (Table 2).
Atherosclerosis (AS) is a common vascular disease with plaque formation being one of its pathological features. An unstable plaque rupture within the coronary artery will lead to thrombosis, which accounts for the foundation of ACS incidence. Meanwhile, the osteoclast-associated receptor (OSCAR) is a type of immunoglobulin receptor expressed in an osteoclast, which is one of the members encoded by the lymphocyte receptor complexes (LRC) family. OSCAR can be markedly expressed in an osteoclast, and it can also be found in monocytes; a discovery which has laid down a molecular basis for understanding the differentiation of a monocyte into an osteoclast. In humans, OSCAR can be expressed as a macrophage, a monocyte and a monocyte-derived dendritic cell (10). Moreover, clinical investigations have suggested that OSCAR may participate in the pathogenesis of rheumatoid arthritis and osteoporosis (5,11,12).
OSCAR can be divided into two types: soluble and membranous. As shown in this study, the sOSCAR in the ACS group is remarkably lower than in the non-ACS group (P=0.005). Multivariate regression analysis indicated that the decreased level of sOSCAR is independently-associated with the presence of ACS. For predicting ACS, the area under the receiver–operating characteristic curve of sOSCAR was 0.691 (0.573–0.793, P=0.002). However, this is an observational study which may not demonstrate the cause-effect relationship between decreased OSCAR levels and ACS; therefore, a prospective follow-up study is needed to clarify the associations between sOSCAR levels and ACS.
Oxidized low density lipoproteins (oxLDL) are formed through the oxidation of low density lipoproteins (LDL) in vivo. This is an important factor that leads to the genesis and the development of AS, and unstable plaque formation (13). Ehara et al. discovered that an elevated oxLDL level was positively correlated with ACS severity (14). Circulating oxLDL-specific markers strongly reflect the presence of ACS. Furthermore, OSCAR has been identified in endothelial cells, responding to the proatherogenic factor of oxLDL (6,7,15). Therefore, we speculate that this association between sOSCAR and oxLDL may explain the correlation between sOSCAR and ACS.
The decreased levels of sOSCAR are independently-associated with ACS, and might be considered as a potential biomarker for the prediction of ACS.
Funding: This work is supported by a grant from the Jiangsu Province’s Key Provincial Talents Program (ZDRCA16019) and grants from the National Natural Science Foundation of China (81570332 and 81370280).
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: This study was approved by the Ethics Committee of The Second Affiliated Hospital of Nantong University (IRB number: 2018041).
- Kim N, Takami M, Rho J, et al. A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J Exp Med 2002;195:201-9. [Crossref] [PubMed]
- Merck E, Gaillard C, Gorman DM, et al. OSCAR is an FcRgamma-associated receptor that is expressed by myeloid cells and is involved in antigen presentation and activation of human dendritic cells. Blood 2004;104:1386-95. [Crossref] [PubMed]
- Kim GS, Koh JM, Chang JS, et al. Association of the OSCAR promoter polymorphism with BMD in postmenopausal women. J Bone Miner Res 2005;20:1342-8. [Crossref] [PubMed]
- Ndongo-Thiam N, de Sallmard G, Kastrup J, et al. Levels of soluble osteoclast-associated receptor (sOSCAR) in rheumatoid arthritis: link to disease severity and cardiovascular risk. Ann Rheum Dis 2014;73:1276-7. [Crossref] [PubMed]
- Herman S, Muller RB, Kronke G, et al. Induction of osteoclast-associated receptor, a key osteoclast costimulation molecule, in rheumatoid arthritis. Arthritis Rheum 2008;58:3041-50. [Crossref] [PubMed]
- Goettsch C, Rauner M, Sinningen K, et al. The osteoclast-associated receptor (OSCAR) is a novel receptor regulated by oxidized low-density lipoprotein in human endothelial cells. Endocrinology 2011;152:4915-26. [Crossref] [PubMed]
- Sinningen K, Rauner M, Goettsch C, et al. Monocytic expression of osteoclast-associated receptor (OSCAR) is induced in atherosclerotic mice and regulated by oxidized low-density lipoprotein in vitro. Biochem Biophys Res Commun 2013;437:314-8. [Crossref] [PubMed]
- American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions, O'Gara PT, Kushner FG, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140. [Crossref] [PubMed]
- Roffi M, Patrono C, Collet JP, et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016;37:267-315. [Crossref] [PubMed]
- Nemeth K, Schoppet M, Al-Fakhri N, et al. The role of osteoclast-associated receptor in osteoimmunology. J Immunol 2011;186:13-8. [Crossref] [PubMed]
- Dharmapatni AA, Algate K, Coleman R, et al. Osteoclast-Associated Receptor (OSCAR) Distribution in the Synovial Tissues of Patients with Active RA and TNF-alpha and RANKL Regulation of Expression by Osteoclasts In Vitro. Inflammation 2017;40:1566-75. [Crossref] [PubMed]
- Crotti TN, Dharmapatni AA, Alias E, et al. Osteoimmunology: Major and Costimulatory Pathway Expression Associated with Chronic Inflammatory Induced Bone Loss. J Immunol Res 2015;2015. [Crossref] [PubMed]
- Li D, Williams V, Liu L, et al. Expression of lectin-like oxidized low-density lipoprotein receptors during ischemia-reperfusion and its role in determination of apoptosis and left ventricular dysfunction. J Am Coll Cardiol 2003;41:1048-55. [Crossref] [PubMed]
- Ehara S, Ueda M, Naruko T, et al. Elevated levels of oxidized low density lipoprotein show a positive relationship with the severity of acute coronary syndromes. Circulation 2001;103:1955-60. [Crossref] [PubMed]
- Crotti TN, Dharmapatni AA, Alias E, et al. The immunoreceptor tyrosine-based activation motif (ITAM) -related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints. Arthritis Res Ther 2012;14:R245. [Crossref] [PubMed]