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Serum lncRNA ITGB2-AS1 and ICAM-1 as novel biomarkers for rheumatoid arthritis and osteoarthritis diagnosis

BMC Medical Genomics volume 17, Article number: 247 (2024) Cite this article

Abstract

Background

The complete circulating long non-coding RNAs (lncRNAs) signature of rheumatoid arthritis (RA) and osteoarthritis (OA) is still uncovered. The lncRNA integrin subunit beta 2 (ITGB2)-anti-sense RNA 1 (ITGB2-AS1) affects ITGB2 expression; however, there is a gap in knowledge regarding its expression and clinical usefulness in RA and OA. This study investigated the potential of serum ITGB2-AS1 as a novel diagnostic biomarker and its correlation with ITGB2 expression and its ligand intercellular adhesion molecule-1 (ICAM-1), disease activity, and severity in RA and primary knee OA patients.

Subjects

Forty-three RA patients, 35 knee OA patients, and 22 healthy volunteers were included.

Results

Compared with healthy controls, serum ITGB2-AS1 expression was upregulated in RA patients but wasn’t significantly altered in knee OA patients, whereas serum ICAM-1 protein levels were elevated in both diseases. ITGB2-AS1 showed discriminative potential for RA versus controls (AUC = 0.772), while ICAM-1 displayed diagnostic potential for both RA and knee OA versus controls (AUC = 0.804, 0.914, respectively) in receiver-operating characteristic analysis. In the multivariate analysis, serum ITGB2-AS1 and ICAM-1 were associated with the risk of developing RA, while only ICAM-1 was associated with the risk of developing knee OA. A panel combining ITGB2-AS1 and ICAM-1 showed profound diagnostic power for RA (AUC = 0.9, sensitivity = 86.05%, and specificity = 91.67%). Interestingly, serum ITGB2-AS1 positively correlated with disease activity (DAS28) in RA patients and with ITGB2 mRNA expression in both diseases, while ICAM-1 positively correlated with ITGB2 expression in knee OA patients.

Conclusion

Our study portrays serum ITGB2-AS1 as a novel potential diagnostic biomarker of RA that correlates with disease activity. A predictive panel combining ITGB2-AS1 and ICAM-1 could have clinical utility in RA diagnosis. We also spotlight the association of ICAM-1 with knee OA diagnosis. The correlation of serum ITGB2-AS1 with ITGB2 expression in both diseases may be insightful for further mechanistic studies.

Highlights

  • • Serum ITGB2-AS1 is a novel potential biomarker of RA that correlates with disease activity.

  • • A predictive panel combining ITGB2-AS1 and ICAM-1 could have clinical utility in RA diagnosis.

  • • Serum ICAM-1 is potentially associated with knee OA diagnosis.

  • • Serum ITGB2-AS1 was correlated with ITGB2 mRNA expression in RA and knee OA patients.

  • • Serum ICAM-1 was correlated with ITGB2 mRNA expression in knee OA patients.

Peer Review reports

Introduction

Rheumatoid arthritis (RA) and osteoarthritis (OA) are two major chronic musculoskeletal conditions that cause a progressive decline in both physical function and quality of life, posing profound medical and socio-economic impediments. RA is a well-known systemic autoimmune disease of the joints with a global incidence of ~ 1% [1]. OA is the most frequently reported joint devastating disease affecting > 500 million people worldwide, with > 22% of adults older than 40 having knee OA, the most common type of OA [2, 3].

Currently, there is no cure for RA and OA, and clinical interventions could only help relieve pain, halt or delay disease progression, and reduce disability, especially when applied early [1, 2]. In addition, the current traditional diagnostic methods of both diseases have serious constraints, including inadequate accuracy for the diagnosis of RA and OA and hazardous exposure to radiography in OA diagnosis [4, 5]. For RA diagnosis, clinicians often use the 2010 American College of Rheumatology/European League Against Rheumatology (ACR/EULAR) classification system, which has low specificity (61%), may fail to identify patients who have very early presentations of RA or inactive disease, and is challenging for seronegative RA patients [6]. Thus, identifying novel potential biomarkers and therapeutic targets is urgent for accurate diagnosis and targeted therapy of RA and OA.

The pathogenetic processes of RA and OA are composite and distinct; however, they share synovial inflammation and immune dysregulation [7,8,9]. In RA, immune activation amplifies synovial membrane inflammation and boosts joint swelling with leukocytes entering the synovial compartment [9]. OA is a whole-joint disorder that results from cartilage degeneration mostly arising from mechanical factors over time, leading to osteophytosis, subchondral bone thickening, synovial membrane inflammation, meniscus injury, and ligament degeneration [10, 11]. Strikingly, OA is evoked by the recruitment and infiltration of activated macrophages and T-cell subpopulations in the synovial cavity [12, 13]. These inflammatory and immune-triggered changes are mediated by the interplay between environmental, genetic, and epigenetic factors, culminating in progressive joint destruction in both diseases [1, 14]. Recently, the role of epigenetics in the pathogenesis of inflammatory arthritis, including RA and OA, has received much attention to develop novel targets for their theragnostics [15].

Long non-coding RNAs (lncRNAs) are among several epigenetic mechanisms that evolved to explain the pathobiology of RA and OA [15,16,17]. Overwhelming evidence uncovered the differential expression of several lncRNAs at the cellular and tissue levels in human RA and OA conditions, suggesting the undefined roles of lncRNAs in their development and progression. Indeed, lncRNAs are impeccable regulators of the inflammatory response and have been mechanistically linked to inflammatory joint pathology, and emerged as promising biomarkers [16,17,18,19]. However, lncRNA research in inflammatory joint disease, including RA and OA, is still a developing field, and the role, expression pattern, and clinical significance of many lncRNAs in RA and OA are largely unknown.

The lncRNA integrin subunit beta 2 (ITGB2)-anti-sense RNA 1 (ITGB2-AS1), located in chromosome 21q22.3, is a newly identified lncRNA that has been reported among the highly expressed lncRNAs in monocytes and has been shown to regulate T-cell and B-cell activation [20]. Furthermore, high expression of ITGB2-AS1 was concordant with multiple cancer genes in acute lymphoid leukemia and lymphoma and was suggested as a biomarker [21]. Moreover, ITGB2-AS1 has also been shown to be upregulated in breast cancer [22], pancreatic ductal adenocarcinoma [23], osteosarcoma [24], and clear cell renal cell carcinoma tissues and cell lines [25], indicating its oncogenic role. Notably, ITGB2-AS1 predicted poor outcomes in osteosarcoma and clear cell renal cell carcinoma patients [24, 25]. However, the ITGB2-AS1 expression pattern in RA and OA was not previously investigated, leaving a gap in knowledge regarding its pathogenic role, predictive and discriminative ability, and relevance to the clinical setting of both diseases.

Given the sequence homology between ITGB2-AS1 and ITGB2 (CD18), a common β2 subunit of β2-integrins, ITGB2-AS1 is one of the epigenetic mechanisms affecting ITGB2 expression [22]. Consistent with ITGB2-AS1, ITGB2 mediates immune cell migration, adhesion, and trafficking during inflammation through multiple interactions with adhesion and extracellular matrix molecules [26, 27]. Interestingly, in our previous study, we identified ITGB2 as a disease-associated gene of both RA and OA; its mRNA expression was upregulated in the sera of both RA and knee OA patients and showed profound diagnostic potential for both diseases [26]. We also constructed the ITGB2 protein-protein interaction network that mainly comprised intercellular adhesion molecules (ICAM)-1, 2, and 3 and vascular cell adhesion molecule-1 (VCAM-1) [26]. In particular, ICAM-1 (CD54) is the main ligand for leukocyte β2-integrins [28, 29]. In inflamed tissues, ICAM-1 expressed on endothelial cells binds to the β2-integrins; αLβ2 (lymphocyte function-associated antigen-1, LFA-1) and αMβ2 (macrophage-1 antigen, Mac-1) on leukocytes and facilitates their transendothelial migration to the inflammation site. Given its role in mediating leukocyte migration, ICAM-1 upregulation has been associated with various inflammatory, neuroinflammatory, autoimmune, and allergic diseases [29, 30]. However, the crosstalk of ITGB2-AS1 with ITGB2 and its ligand ICAM-1, their diagnostic and discriminative power, and clinical correlations in RA and knee OA are yet to be explored.

In this context, the current study attempted to investigate the expression profile of serum ITGB2-AS1 and explore its potential as a novel diagnostic biomarker, and whether it is clinically correlated with disease activity and severity in RA and primary knee OA patients. In addition, we appraised the correlations of serum ITGB2-AS1 with ITGB2 expression, ICAM-1, and other clinicopathological data.

Subjects and methods

Subjects

This cross-sectional study included one hundred Egyptian participants, aged 50–70 years old, classified as 43 RA patients and 35 primary knee OA patients, in addition to 22 sex- and age-matched healthy participants. Freshly diagnosed and treatment-naïve patients were recruited from the Rheumatology and Immunology Unit of Kasr Al-Ainy Hospital, Cairo, Egypt.

All participants’ full history and clinical assessment have been taken and their medical records have been gathered. The diagnosis of RA was performed according to the 2010 ACR/EULAR classification criteria based on the clinical assessment of joint involvement, serological abnormality as indicated by rheumatoid factor (RF), elevated acute phase response [erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)], and symptoms duration [31]. The disease activity of RA was evaluated by a rheumatologist using the disease activity score 28-joint count (DAS28)-CRP [32]. RA patients who have malignancy or other autoimmune diseases, or who were getting treatment were excluded from the study.

Primary knee OA was diagnosed based on the clinical and radiological investigations reported in the revised criteria of ACR (2016) [33]. The structural features and severity of knee OA were assessed by a rheumatologist based on a radiographic knee X-ray and recorded according to the Kellgren–Lawrence (KL) scale for radiographic classification of OA [34]. OA patients who have any autoimmune or other inflammatory diseases, trauma, or patients who previously received oral or intra-articular injections were excluded from our study.

Ethics declaration

A written informed consent was signed by all participants before the beginning of the study. The ethical approval committee of the Faculty of Pharmacy, Cairo University approved the study protocol as well as the informed consent (approval number: BC2735), which followed the ethical standards of the Helsinki Declaration revised in 2008.

Blood collection and biochemical measurements

Blood samples were withdrawn from all participants in appropriate tubes for whole blood collection and serum separation. Whole anticoagulated blood was used to determine the ESR using Westergren tubes (mm/h). Appropriately stored (– 80 °C) aliquoted serum samples were used for total RNA extraction and investigation of other biochemical parameters. Commercial sandwich ELISA kits (Biovision, USA) were procured for the measurement of serum CRP and RF levels.

RNA extraction

Two hundred microliters of serum were used to extricate total RNA using miRNeasy Mini kit (Qiagen, Germany) with the supplied QIAzol lysis reagent following the manufacturer’s recommendations. The concentration and purity of the eluted RNA were evaluated by measuring the OD260 and OD260/OD280 ratio using Implen NanoPhotometer® P-Class 300 (Implen, Germany). RNA samples of OD260/OD280 = 1.8 to 2 were used in reverse transcription.

Serum ITGB2-AS1 assay using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR)

Using the High-Capacity cDNA Reverse Transcription kit (Applied Biosystems, Thermo Fisher Scientific, San Jose, USA), complementary DNA was synthesized from RNA as directed in the kit’s instructions. In a final volume of 20 µL RT reactions, reverse transcription was attempted on 0.1 µg of total RNA. The following thermal cycler conditions were applied: 10 min at 25 °C, 120 min at 37 °C, and 5 min at 85 °C. The cDNA was stored at – 20 °C until further analysis.

The lncRNA ITGB2-AS1 gene expression (NR_038311, Ensembl ID: ENSG00000227039, Gene ID: 100505746.0) was quantitated using StepOne Applied Biosystems Real-Time PCR System (Thermo Fisher Scientific, San Jose, USA) using the Maxima SYBER Green/ROX qPCR Master Mix (Thermo Fisher Scientific, San Jose, USA), along with custom-made forward and reverse primers (Invitrogen, Carlsbad, USA) for ITGB2-AS1 and GAPDH as the housekeeping gene. GAPDH was set as an internal control for normalizing lncRNAs as previously described [35, 36]. Before customization, the specificity of primers was checked using the NCBI Primer-Blast tool which is sensitive enough and reliable. The following were the primers’ sequences used in the study: ITGB2-AS1-forward 5′-AGGAGATGGAACGAGGAAA-3′, ITGB2-AS1-reverse 5′-TTAGTGGTCTGCGAAGGTG-3′, GAPDH-forward 5′-GGCCCTGACAACTCTT-TTCATC-3′, and GAPDH-reverse 5′-CTGGTTGAGCACAGGGTACT-3′. The thermal cycling conditions applied in quantitative PCR were 95 °C for 10 min followed by 40 cycles of 15 s at 95 °C and 60 s at 60 °C.

For each qPCR experiment, we performed three technical replicates. A negative control was used in each run. A melting curve analysis was performed to ensure the specificity of PCR products and that primer dimers were absent. Relative expression of ITGB2-AS1 was calculated using the ΔΔCt method and presented as fold change (2−ΔΔCt).

Determination of serum ICAM-1 protein levels

Serum ICAM-1 levels were measured by sandwich ELISA technique using the ICAM-1 human ELISA Kit (Catalog# K7522-100, Biovision, USA) on Biochrom, ASYS ELISA reader (USA). The results are expressed as picograms per milliliter.

Statistical analysis

The GraphPad Prism version 6 (GraphPad Software, CA) was used to conduct the statistical analyses. Data are presented as number (percentage), mean ± standard deviation (SD), or median (25–75% percentiles) when proper. The χ2 test was used for comparison of categorical data. Shapiro-Wilk and Kolmogorov-Smirnov normality tests were implemented to check the normal distribution of continuous variables, and then they were compared using the one-way ANOVA and Tukey post-hoc test or Kruskal-Wallis and Dunn’s multiple comparison tests when suitable. The receiver-operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic accuracy of studied biomarkers. We regarded the area under the curve (AUC) 0.6 to 0.69 as a significant discriminator, 0.7 to 0.89 as a potential discriminator, and AUC ≥ 0.9 as an excellent discriminator. Assessment of studied parameters with the risk of developing RA or knee OA was performed using univariate and multivariate analyses with adjustment with age and sex as confounders. The correlation analysis was computed using Spearman correlation. For all tests, a two-tailed P-value < 0.05 was set as the statistical significance level.

The sample size was initially estimated before the start of the study using the G Power Software version 3.1.9.7. We employed the F test (ANOVA) assuming a population variance (standard deviation) of ± 0.5, an effect size f = 0.4, three independent groups, type I error α = 0.05, and type II error β = 0.2. With these postulations, a minimum total sample size of 66 (22 per group) yielded a power (1-β) of 80%.

Results

Patients’ characteristics

The demographic, laboratory, and clinical data of the study groups are displayed in Table 1. Knee OA patients had a significantly higher age than RA patients (P = 0.0009), but both groups were age-matched to the healthy controls (P > 0.05). CRP, ESR, and RF were higher in RA patients than those in healthy controls or OA patients (P < 0.0001 for each), whereas their levels were comparable in OA patients and healthy controls (P > 0.05). Regarding disease activity, the recruited RA patients had variable disease activity ranging from low to high, with 55.8% of them having a high disease activity (DAS28 ≥ 5.1). Based on an X-ray, 14.3% of knee OA patients had severe disease (KL = 4).

Table 1 Characteristics of the study groups
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Serum ITGB2-AS1 expression is differentially expressed in RA patients but not in knee OA patients

As shown in Fig. 1, serum ITGB2-AS1 expression was significantly upregulated in RA patients compared with healthy controls with a median fold change of 1.67 (P = 0.0053). However, there was no significant difference in serum ITGB2-AS1 levels between knee OA patients and healthy controls (P > 0.99). Serum ITGB2-AS1 expression levels were profoundly higher in RA patients than those in knee OA patients by 81% (P = 0.025).

To note, the average Ct values for ITGB2-AS1 and GAPDH for the studied groups expressed as mean ± SD were as follows: control = 30.9 ± 3.16, RA = 30.98 ± 2.64, and knee OA = 30.05 ± 2.79 for ITGB2-AS1, and control = 30.93 ± 3.13, RA = 32.33 ± 2.27, and knee OA = 30.51 ± 2.62 for GAPDH.

Fig. 1
figure 1

Serum ITGB2-AS1 expression profile in RA and knee OA patients comparing with healthy controls. Data are presented as box plot for RA (n = 43), knee OA (n = 35) patients, and healthy controls (n = 22); the box represents the 25–75% percentiles; the line inside the box represents the median and the upper and lower lines representing the minimum and maximum. Kruskal-Wallis followed by Dunn’s multiple comparison tests were used for data analysis. P < 0.05 is considered statistically significant. ITGB2-AS1, integrin subunit beta 2-anti-sense RNA 1; OA, osteoarthritis; RA, rheumatoid arthritis

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Serum ICAM-1 protein levels are upregulated in RA and knee OA patients

Fig. 2
figure 2

Serum ICAM-1 protein levels in RA and knee OA patients comparing with healthy controls. Data are presented as box plot for RA (n = 43), knee OA (n = 35) patients, and healthy controls (n = 22); the box represents the 25–75% percentiles; the line inside the box represents the median and the upper and lower lines representing the minimum and maximum. Kruskal-Wallis followed by Dunn’s multiple comparison tests were used for data analysis. P < 0.05 is considered statistically significant. ICAM-1, intercellular adhesion molecule-1; OA, osteoarthritis; RA, rheumatoid arthritis

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Figure 2 shows the significant increase in serum ICAM-1 levels in both RA (P = 0.0028) and knee OA patients (P = 0.0004) compared with levels in the healthy control group. However, there was no significant difference in serum ICAM-1 levels between RA and knee OA patients (P = 0.831).

Serum ITGB2-AS1 and ICAM-1 levels show diagnostic potential in RA and knee OA

ROC analysis showed that serum ITGB2-AS1 expression levels distinguished RA patients from healthy controls with an AUC = 0.772, 95% CI = 0.695 to 0.885, P = 0.0025, and a sensitivity of 54.85% and a specificity of 100% at a cut-off value > 1.573-fold (Fig. 3A). Besides, serum ITGB2-AS1 expression levels discriminated RA patients from knee OA patients with an AUC = 0.7, 95% CI = 0.585 to 0.815, P = 0.0072, and a sensitivity of 54.84% and a specificity of 80% at a cut-off value > 1.631-fold (Fig. 3B).

ROC analysis also unveiled that serum ICAM-1 protein levels distinguished RA patients from healthy controls with an AUC = 0.804, 95% CI = 0.699 to 0.909, P < 0.0001, and a sensitivity of 66.76% and a specificity of 91.67% at a cut-off > 2000 pg/mL (Fig. 3C). Besides, serum ICAM-1 level profoundly distinguished knee OA patients from healthy controls with an AUC = 0.914, 95% CI = 0.841 to 0.987, P < 0.0001, and a sensitivity of 82.86% and a specificity of 91.67% at a cut-off value > 2064 pg/mL (Fig. 3D). The diagnostic performance of ICAM-1 was superior in knee OA to RA (difference = 0.11, P = 0.02). The positive and negative predictive values for ITGB2-AS1 and ICAM-1 are shown in Table 2.

Fig. 3
figure 3

Diagnostic performance of serum ITGB2-AS1 and ICAM-1 levels in RA and knee OA patients. A ROC curve analysis was conducted to show the diagnostic and discriminative potential in RA (n = 43), knee OA (n = 35), and healthy controls (n = 22). (A) ITGB2-AS1 RA vs. control, AUC = 0.772, P = 0.0025. (B) ITGB2-AS1 RA vs. knee OA, AUC = 0.7, P = 0.0072. (C) ICAM-1 RA vs. control, AUC = 0.804, P < 0.0001. (D) ICAM-1 knee OA vs. control, AUC = 0.914, P < 0.0001

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Table 2 Diagnostic performance of serum ITGB2-AS1 and ICAM-1 levels in RA and knee OA
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Serum ITGB2-AS1 and ICAM-1 levels are associated with the risk of developing RA in logistic regression analysis

We computed univariate and multivariate logistic regression analyses to predict the risk of developing RA (Table 3). ITGB2 mRNA expression levels in the recruited patients were included based on the results of our previous study [26], as logistic regression wasn’t analyzed before for ITGB2 in RA and OA. In the univariate analysis, serum levels of ITGB2-AS1, ITGB2 mRNA expression, and ICAM-1 protein levels were significantly associated with the risk of developing RA (P < 0.05). In the multivariate analysis, only serum levels of ITGB2-AS1 and ICAM-1 were independent variables significantly associated with the risk of developing RA. The model was adjusted with age and sex as covariates.

Table 3 Logistic regression analysis to predict the risk of RA
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A panel combining serum ITGB2-AS1 and ICAM-1 performs better in RA diagnosis

Constructing a model combining the two predictor markers ITGB2-AS1 and ICAM-1 revealed that a panel of these two markers (Fig. 4) discriminated patients with RA from healthy controls with an AUC of 0.9 (P < 0.0001) and an optimal sensitivity and specificity of 86.05% and 91.67%, respectively, at the best cut-off value calculated as the value at which there is a maximum sum of sensitivity and specificity. Intriguingly, the panel outperforms each marker alone in RA diagnosis (the AUC difference from ITGB2-AS1 = 0.128, P = 0.013 and the difference from ICAM-1 = 0.096, P = 0.049).

Fig. 4
figure 4

Diagnostic performance of a panel of serum ITGB2-AS1 combined with ICAM-1 levels in RA patients. A ROC curve analysis was conducted using a logistic regression model (unadjusted logit (p) = − 8.7 + 1.4207*ITGB2-AS1 + 0.0038*ICAM-1) to show the diagnostic potential of ITGB2-AS1 + ICAM-1 combination in RA (n = 43) vs. healthy controls (n = 22). The AUC of the ITGB2-AS1 + ICAM-1 panel = 0.9, P < 0.0001. ICAM-1, intercellular adhesion molecule-1; ITGB2-AS1, integrin subunit beta 2-anti-sense RNA 1

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Serum ICAM-1 protein levels are associated with the risk of developing knee OA in multivariate logistic regression analysis

When testing the predictor variables of knee OA diagnosis (Table 4), univariate logistic regression analysis revealed serum ITGB2 mRNA expression and ICAM-1 as significant variables. However, the multivariate logistic analysis, adjusted with age and sex as covariates, revealed serum ICAM-1 protein levels only as a significant variable associated with the risk of developing knee OA.

Table 4 Logistic regression analysis to predict the risk of knee OA
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Remarked correlations shape the relation of the studied parameters with each other and/or with the clinical characteristics of studied patients

There were multiple significant correlations for serum ITGB2-AS1 expression or ICAM-1 protein level with ITGB2 mRNA expression and clinical parameters (Table 5). In RA patients, we found a significant positive correlation between serum ITGB2-AS1 and ITGB2 mRNA expression levels (r = 0.649, P < 0.0001). Interestingly, serum ITGB2-AS1 was also correlated with disease activity (DAS28) in RA patients (r = 0.394, P = 0.009). In OA, a positive correlation was also noted between ITGB2-AS1 and ITGB2 mRNA expression (r = 0.35, P = 0.038). Interestingly, a positive correlation between ICAM-1 protein level and ITGB2 mRNA expression was documented in knee OA patients (r = 0.446, P = 0.007).

Table 5 Correlations of serum ITGB2-AS1 and ICAM-1 with ITGB2, demographic, biochemical, and clinical characteristics of RA and knee OA patients
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Discussion

The identification of novel biomarkers of RA and OA is clinically imperative due to the serious limitations of the current diagnostic methods. Among the current drawbacks are the insufficient accuracy of the classic markers such as RF and anti-citrullinated protein/peptide antibody (ACPA) for RA diagnosis [4] and radiography for OA diagnosis, along with the slow structural changes detected in radiography over time and its exposure hazards [5]. Indeed, the documented sensitivity of RF in RA ranges from 26 to 90%, with a pooled sensitivity of 69% and a specificity of 85% in a meta-analysis [37]. Besides, RF tests have a reported sensitivity and specificity of about 79.9% and 72.4%, respectively, in another publication [38]. ACPA testing has a higher specificity than RF tests in RA [39]; however, RF and ACPA can appear in patients with other pathologies and healthy donors [40]. Indeed, assays of anti-cyclic citrullinated peptide 2 (anti-CCP2), which belongs to ACPAs, have high specificity (90–98%) but low to moderate sensitivity ranging from 55 to 80% for RA [41]. In a meta-analysis, anti-CCP had a pooled sensitivity of 67% and a specificity of 95% for a diagnosis of RA [37]. Despite this high specificity, ACPA may be found in some patients with other rheumatic autoimmune diseases, including psoriatic arthritis, systemic lupus erythematosus, and Sjögren’s syndrome [41]. While only 48% of anti-CPP 3.1-positive patients had a diagnosis of RA, suggesting a lower-than-expected positive predictive value of the anti-CCP 3.1 level with an RA diagnosis [42]. Additionally, using ESR or CRP as a diagnostic biomarker in RA has been proven to be less powerful due to its low sensitivity and specificity [43]. In RA, the sensitivities of ESR and CRP ranged from 53 to 55% and 42 to 65%, respectively, in different populations [44]. Moreover, in RA registry data for over 9000 patients, over 50% did not have an elevation of ESR or CRP [45]. In RA patients, an elevation of both ESR and CRP had a specificity of about 76% and a sensitivity of about 60% [46].

Lately, lncRNAs have been highlighted as potential circulating biomarkers of RA and knee OA [16,17,18,19]. Here, we identified a novel panel combining the lncRNA ITGB2-AS1 with ICAM-1 for RA diagnosis with an optimal sensitivity of 86.05% and specificity of 91.67%, thus outdoing the aforementioned traditional markers and surpassing ITGB2-AS1 and ICAM-1 alone. In particular, the diagnostic accuracy of this panel for RA surpasses that reported for traditional markers (RF, CRP, and ESR) and appears to have higher sensitivity but comparable specificity with ACPA. These results could explicitly furnish the clinical diagnosis and therapeutic repertoire of RA.

To the best of our knowledge, this is the first study that discloses the circulating expression profile of the lncRNA ITGB2-AS1 in RA and knee OA patients and pinpoints its disease-specific profile in RA relative to OA. We also introduce circulating ITGB2-AS1 as a potential biomarker associated with RA diagnosis. Besides, the potential discriminative ability of ITGB2-AS1 between RA and knee OA is noticeable. Strikingly, combining serum ITGB2-AS1 with ICAM-1 levels performed higher than either marker alone in RA diagnosis. Remarkably, serum ITGB2-AS1 expression was correlated with disease activity in RA patients, denoting its relation to the disease pathology. Together, these data spotlight the relevance of serum ITGB2-AS1 to the clinical setting regarding RA diagnosis, patients’ classification, and treatment plans.

The present study demonstrated an upregulation of serum ITGB2-AS1 in RA compared to healthy controls and knee OA patients. Mechanistically, previous studies have shown that ITGB2-AS1 increases the expression of ITGB2 mRNA and protein and activates integrin-related focal adhesion kinases (FAK) signaling [22, 47]. When kinases’ activity decreases, integrins function via recruiting and activating kinases; among these kinases are FAKs [48, 49]. This could explain the observed strong positive correlation between serum ITGB2-AS1 and ITGB2 expression in RA patients. Indeed, markedly increased ITGB2 expression was previously observed in RA patients and was associated with the minor CC genotype of the ITGB2 rs2070946 genetic variant [26]. Thus, ITGB2-AS1 could be another mechanism that positively regulates ITGB2 expression. Interestingly, the current results portray the correlation between serum ITGB2-AS1 and RA disease activity, which coincides with our previous finding of ITGB2 correlation with disease activity as well as RF levels in RA patients [26]. Altogether, this emphasizes the role of the ITGB2-AS1/ITGB2 axis in the pathogenesis of RA that could be extrapolated to the clinical setting.

The mechanism of ITGB2-AS1 was expatiated in bone-related tumors and other cancers. ITGB2-AS1 expression is upregulated in osteosarcoma tissues; knockdown of ITGB2-AS1 inhibited the proliferation and induced apoptosis of osteosarcoma cells, while high ITGB2-AS1 expression was associated with poor prognosis in osteosarcoma patients [24]. Additionally, ITGB2-AS1 promoted the migration and invasion of breast cancer cells by increasing ITGB2 subunit mRNA and protein expression [22]. Furthermore, the oncogenic effect of ITGB2-AS1 in clear cell renal cell carcinoma was mediated by the miR-328-5p/high mobility group protein A1 (HMGA1) axis [25]. Moreover, ITGB2-AS1 enhanced cisplatin resistance in non-small cell lung cancer by suppressing ferroptosis through activation of the FOS Like 1, AP-1 transcription factor subunit (FOSL2)/nicotinamide phosphoribosyltransferase (NAMPT) axis [50]. Besides, ITGB2-AS1 was correlated with the immune score, stromal score, and various immune signatures in acute myeloid leukemia [51]. Collectively, these data indicate the role of ITGB2-AS1 in cell proliferation, migration, invasion, apoptosis, inflammatory response, and immune activation. Interestingly, these pathways are interrelated to the pathogenesis of RA, as shown in fibroblast-like synoviocytes, and were also shown to be targets of other lncRNAs in these cells [52]. However, the precise mechanism of ITGB2-AS1 in RA should be further investigated at the cellular level.

The differential expression of ITGB2-AS1 between RA and knee OA suggests its pathology-specific nature. Similarly, unique expression profiles of lncRNAs have been demonstrated in RA but not in OA [53]. Also, OA-specific non-coding RNAs, including lncRNAs, have been recently unraveled [54]. However, consistent with RA, we also recorded a positive correlation of serum ITGB2-AS1 with ITGB2 expression in OA patients. Given that serum ITGB2 expression was previously shown to be elevated in knee OA patients [26], such a correlation might indicate concordant expression of ITGB2-AS1 and ITGB2 in OA. Our data recapitulate the notion of the clinical usefulness of non-coding RNAs in discriminating inflammatory and autoimmune diseases and their correlation with disease pathogenesis, activity, and severity [45].

The current study showed a marked increase in serum ICAM-1 levels in RA and OA patients. Similarly, RA-induced rats showed a marked increase in serum levels of ICAM-1 as compared with the control group [55]. Serum ICAM-1 is also elevated in RA patients [56]. Likewise, studies have revealed higher levels of ICAM-1 in OA synovial tissue than in healthy tissue [57,58,59]. The observed elevation in serum ICAM-1 in RA and knee OA is consistent with the elevation of ITGB2 expression, the main leukocyte receptor for endothelial ICAM-1 that facilitates leukocyte adhesion and transmigration to the inflammatory site. Indeed, ICAM-1 was positively correlated with ITGB2 mRNA expression in our knee OA patients. This correlation supports the role of the ITGB2/ICAM-1 axis in inflammatory joint disease.

The inflammatory process is known to induce the activation of endothelial cells, causing endothelial dysfunction. Such a process induces increased expression of leukocyte adhesion molecules like ICAM-1 [60]. Furthermore, the acute inflammatory reaction is characterized by an increase in vascular permeability and cellular infiltration. At the inflammatory site, the interaction between leukocytes and the vascular endothelium-upregulated cell adhesion molecules leads to an extra accumulation of fluid and leukocytes. ICAM-1 enhances the attachment and transmigration of circulating monocytes to the endothelial cells, resulting in the main event of inflammation [55]. Besides, ICAM-1 promotes monocyte recruitment into the synovial tissue via binding leucocyte integrins [57]. This emphasizes the role of ICAM-1 in the pathogenesis of inflammatory diseases, including RA and OA. Interestingly, serum ICAM-1 was associated with the risk of developing RA or knee OA in multivariate analysis, suggesting its clinical usefulness as a biomarker of inflammatory joint diseases. In addition, the ICAM-1 combination with serum ITGB2-AS1 expression maximized their accuracy in RA diagnosis. However, ICAM-1 was not correlated with RA disease activity or knee OA severity in this study. In contrast, serum ICAM-1 was correlated with disease activity in RA patients in an earlier study [56]. Soluble ICAM-1 was also found to be elevated in the sera of RA patients and correlated with disease activity [61]. This contradictory finding could be explained by differences in sample size, confounding factors, and measuring soluble (cleaved) versus intact ICAM-1.

While several studies pointed at the usefulness of non-coding RNAs and their related molecules in the clinical setting of autoimmune and inflammatory diseases [18, 19, 62], the present data spotlight the correlation of serum ITGB2-AS1 with RA disease activity and its potential diagnostic ability and pinpoint a highly accurate panel of the lncRNA ITGB2-AS1 + ICAM-1 for RA diagnosis. This study also highlights serum ICAM-1 as a predictor of OA diagnosis.

Several limitations exist in this study. The sample size is considered moderate, so further studies are warranted to validate our results with a larger sample size. Furthermore, selection bias was inevitable as blood samples were gathered from a single hospital. Third, we only conducted an in vivo study and didn’t examine the mechanistic relationship of ITGB2-AS1 with the ITGB2/ICAM-1 axis in vitro. Fourth, ACPA testing is expensive in Egypt; thus, it is not considered a routine test, and its cost is not suitable for the majority of patients. Therefore, we relied on the clinical assessment of joints, one acute phase reactant (ESR or CRP), and RF serological testing for RA diagnosis using the ACR/EULAR guidelines, which require the results of at least one serology test. Nevertheless, our findings may aid in the risk stratification, timely diagnosis, and management of both RA and OA and explicitly open a new avenue for developing novel therapies. Future studies to determine the functional role and other target genes of ITGB2-AS1 will be insightful, as will joint tissue expression profiling of this lncRNA for which functional roles within key inflammatory pathways have been determined.

Conclusion

Our study is the first to embrace serum ITGB2-AS1 expression as a potential diagnostic biomarker of RA that correlates with disease activity and suggests a panel combining serum ITGB2-AS1 and ICAM-1 as a clinically useful marker for RA diagnosis. This study also spotlights ICAM-1 as a marker associated with knee OA diagnosis that might be useful in a clinical situation. The correlation of serum ITGB2-AS1 with ITGB2 expression in both RA and OA may be insightful for further mechanistic studies. These data might afford better opportunities for risk stratification and timely diagnosis in precision medicine and could pave the way for novel therapeutics for targeted therapy.

Data availability

All data generated or analyzed during this study are included in the published article.

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Acknowledgements

The authors are grateful for all participants in the work and technicians who helped in carrying out the practical experiments.

Funding

This paper was partially supported by the Faculty of Pharmacy, Cairo University research fund.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Cairo University, 23 Kasr El-Ainy Street, Cairo, 11562, Egypt

    Aliaa M. Selim, Maha M. El-Sawalhi, Nabila A. Ismail & Mahmoud A. Senousy

  2. Department of Rheumatology and Clinical Immunology, Internal Medicine, Kasr Al-Ainy, Faculty of Medicine, Cairo University, Cairo, Egypt

    Yumn A. Elsabagh

  3. Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt

    Mahmoud A. Senousy

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Contributions

Aliaa M. Selim: Investigation concerning data collection of the previously published research on the subject, performing the experimental work, formal analysis of the results, conducting the statistical analysis and data visualization, and writing the original draft. Yumn A. Elsabagh: Sample collection and methodology. Maha M. El-Sawalhi: Suggesting the idea of the research and the plan to perform it, establishing the experimental design, supervising the study, validation of the experimental results, and reviewing data presentation. Nabila A. Ismail: Suggesting the idea of the research and the plan to perform it, establishing the experimental design, supervising the study, validation of the experimental results, and reviewing data presentation. Mahmoud A. Senousy: Conceptualized the study, participated in the study design, supervised the practical work and data investigation, conducted the statistical analysis and data visualization, edited and revised the manuscript.

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Correspondence to Aliaa M. Selim or Maha M. El-Sawalhi.

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Selim, A.M., Elsabagh, Y.A., El-Sawalhi, M.M. et al. Serum lncRNA ITGB2-AS1 and ICAM-1 as novel biomarkers for rheumatoid arthritis and osteoarthritis diagnosis. BMC Med Genomics 17, 247 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12920-024-01993-6

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