Expression levels of CXCR4 and CXCL12 in patients with rheumatoid arthritis and its correlation with disease activity
- Authors:
- Published online on: June 26, 2020 https://doi.org/10.3892/etm.2020.8950
- Pages: 1925-1934
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Copyright: © Peng et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Rheumatoid arthritis (RA) is a common systemic autoimmune disease (1). The primary pathological manifestations of RA are chronic synovium inflammation and pannus formation, which can lead to swelling and deformities in the joints of patients (2). These symptoms can later lead to disability, which may cause a loss of work time, which can create a burden on society and the families of patients (3). The pathogenesis of RA is complex, involving many types of cells, including macrophages, T and B cells, fibroblasts, chondrocytes and dendritic cells (4). Despite study into the role of many genes and mechanisms underlying the development of RA, there is still no clear predisposing factor (5-7).
Chemokines are small protein cytokines, and their main function is to induce leukocytes aggregation to form inflammatory lesions, via directional migration, for participation in the inflammatory response (8). Previous studies have demonstrated that many chemokines are highly expressed in the joint synovial fluid or peripheral blood of patients with RA, which suggests that chemokines may be associated with RA pathogenesis (9,10).
C-X-C motif chemokine ligand 12 (CXCL12) is mainly produced by stromal cells and is a key factor for the activation and migration of inflammatory cells to synovial tissues (11). CXC receptor 4 (CXCR4) is a natural receptor of CXCL12(12). The chemokine CXCL12 can participate in the immune response to RA by mediating the migration and activation of T and B cells in immune cells (13). CXCL12 can also be secreted and produced by joint synovial cells, while CXCR4 can be expressed on the surface of articular chondrocytes (14,15). The activation of CXCR4 and CXCL12 can induce the secretion of a variety of inflammatory factors from articular chondrocytes, leading to apoptosis and destruction of chondrocytes (16,17). Previous studies have demonstrated that CXCR4 and CXCL12 together can serve an important role in lupus erythematosus (18-20). These aforementioned studies indicated that CXCR4 and CXCL12 are closely associated with autoimmune diseases.
Although previous studies have indicated that the expression of CXCL12 in the joint synovial membranes was significantly higher in the patients with RA compared with healthy controls (21), there are relatively few studies on the relationship between CXCR4 and CXCL12, and disease activity in patients with RA. Therefore, the present study investigated the expression levels of CXCR4 and CXCL12 in the serum and joint synovial fluid of patients with RA, and correlation analyses was performed to examine this data with clinical indicators. In addition, the present study investigated the roles of CXCR4 and CXCL12 in the occurrence and development of RA, and the relationship between CXCR4, CXCL12 and disease activity, to identify accurate evaluation indicators for use in patients with RA.
Materials and methods
Patient data
Using a random number table method, 60 patients (male patients, 34; female patients, 26) with RA were recruited and randomly selected as the study group from the Rheumatology and Immunology Department of First People's Hospital of Jingzhou from January 1 to December 31, 2018. The age distribution was 32-60 years old. The average age of all patients was 54.31±5.89 years. Another 60 patients (male patients, 32; female patients, 28) with osteoarthritis, recruited from The First People's Hospital of Jingzhou hospital were selected as the control group.
Patients were selected based on inclusion and exclusion criteria. Patients who met the RA diagnostic criteria revised by The American College of Rheumatology in 1987(22) were included in the study group, and patients who met the guidelines on management of osteoarthritis of the hand, hip and knee by the American College of Rheumatology (23) were included in the control group. Patients were excluded if they had any joint infection, severe liver or kidney dysfunction, cognitive or communication disorders, other autoimmune diseases or malignant tumors, or those who declined to participle. All patients agreed to participate in the experiment and signed an informed consent agreement. This experiment has been approved by the Hospital Ethics Committee of First People's Hospital of Jingzhou.
Specimen extraction
A total of 5 ml fasting venous blood was obtained from all patients and centrifuged at 1,500 x g for 10 min at 4˚C. The serum was collected following centrifugation (1,500 x g for 10 min at 4˚C) and stored at -80˚C. A total of 500 µl joint fluid specimens were collected by outpatient joint punctures or knee joint surgery, and stored at -80˚C for subsequent analysis. Western blotting (WB) and ELISA were used to detect the expression levels of CXCR4 and CXCL12, respectively, in serum and joint fluid.
Detection of CXCR4 expression level using WB
200 µl Radioimmunoprecipitation assay buffer (Cell Signaling Technology, Inc.) was added to the serum and joint fluid specimens collected from patients. The cells were lysed and the total protein of each group was collected. BCA assays were used to determine the protein concentration. After collection, the protein was boiled in water for 8 min at 100˚C. A total of 20 µg protein was loaded into the 10% SDS-PAGE gel and run at 140 V for 2 h. Subsequently, the protein was transferred to a PVDF membrane at 300 mA for 2 h, and PVDF membrane was blocked with 5% skimmed milk powder for 2 h at room temperature. The membranes were probed with the primary antibody targeting CXCR4 (1:1,000; Abcam; cat. no. ab227767) incubated overnight at 4˚C. The antibody GAPDH (1:500; Wuhan Fine Biotech Co., Ltd.; cat. no. FNab03342) was added and incubated overnight at 4˚C, then the membrane was probed with horseradish peroxidase (HRP)-labeled goat anti-rabbit secondary antibodies (1:5,000; Abcam; cat. no. ab97080) at room temperature for 2 h. Subsequently, an enhanced chemiluminescence (ECL) developer (Invitrogen; Thermo Fisher Scientific, Inc.) was used to develop the protein bands. Filter paper was used to absorb excess liquid from the film and protein bands were developed for film-imaged using ECL. The protein bands were scanned and analyzed using Quantity One software (v4.6.6; Bio-Rad Laboratories, Inc.), where the relative expression level of the protein = the gray value of the target protein band/the grey value of the GAPDH protein band.
Detection of CXCL12 expression in serum and joint fluid of patients using ELISA
The ELISA kit was purchased from Quanzhou Ruixin Biotechnology Co., Ltd. (cat. no. 13236). A total of 50 µl of the diluted standard and samples were added into each reaction well, followed by 50 µl biotin-labeled antibodies (all provided as part of the aforementioned kit). These samples were incubated at 37˚C for 1 h and then washed using the wash buffer, 4 times for 5 min each time. Streptomycin-HRP conjugate from the aforementioned kit was added and incubated for 30 min at room temperature. Subsequently, a total of 50 µl substrates provided by the aforementioned kit were added and incubated for 10 min at 37˚C. Subsequently, 50 µl terminating solution, provided by the aforementioned kit, was added to each well and the OD values were measured at 450 nm.
Detection of routine detection indexes in patients with RA
The erythrocyte sedimentation rate (ESR) from the patients with RA was detected using the Westergren's method (24) using an automatic erythrocyte sedimentation rate tester (Plyson cat. no. LBY-XC40B). C-reactive protein (CRP) and the rheumatoid factor (RF) were detected using rate scatter nephelometry (25) using an IMMAGE rate scattering turbidity analyzer (UniCel DxC800; Beckman Coulter, Inc.).
Outcome measures
The outcome measures were as follows: i) The levels of CXCR4 and CXCL12 in serum and joint fluid were compared between the study and control groups; ii) patients with RA were divided based on their disease activity score 28 (DAS28) scores (13) into the remission group (28 cases; ≤2.6 points) and the active group (32 cases; >2.6 points), which were evaluated from four aspects, including the number of tender joints, the number of swollen joints and the erythrocyte sedimentation rate. DAS28 values range from 2.0-10.0(13). A DAS28 <2.6 is interpreted as 'remission'; and iii) CXCR4 and CXCL12 expression levels in the serum and joint fluid of patients were compared. Correlations were analyzed between CXCR4 and CXCL12 expression levels, and ESR, CRP, DAS28 scores and RF in patients with RA.
Statistical analysis
SPSS 18.0 statistical software (SPSS Inc.) was used to analyze the experimental data. Data are presented as the mean ± standard deviation. A χ2 test was used to analyze categorical data. An independent t-test was used for comparison between two groups. One-way ANOVA with a post-hoc LSD test was used for comparison among three groups. Spearman's correlation was used to analyze the correlation between CXCR4 and CXCL12 expression levels. The figures in this study were drawn using Graph Pad Prism 6 software (GraphPad Software, Inc.). P<0.05 was considered to indicate a statistically significant difference.
Results
Patient data
There were no significant differences between sex, age or body mass index in the two groups (Table I).
CXCR4 and CXCL12 expression levels among the study and control groups
The serum CXCR4 expression levels of the study group were 5.12±1.04 and 3.62±0.54, and the serum CXCL12 expression levels were 8.28±1.23 and 7.31±1.69. The joint fluid CXCR4 expression levels of the control group were 3.05±1.11 and 2.13±0.63, and the joint fluid CXCL12 expression levels were 5.14±1.12 and 4.54±1.25. The present results suggested that CXCR4 and CXCL12 expression levels in the serum and articular fluid of the study group were significantly higher compared with the control group (P<0.05; Tables II and III; Figs. 1 and 2).
CXCR4 and CXCL12 expression levels among the RA, remission and control groups
The serum CXCR4 expression levels of the RA-active group were 7.85±1.21 and 6.71±0.69, and the serum CXCL12 expression levels were 10.82±1.33 and 9.46±1.59. CXCR4 expression levels of the RA-remission group were 3.33±1.05 and 2.41±0.57, and CXCL12 expression levels were 5.18±1.15 and 4.74±1.39. The joint fluid CXCR4 expression levels of the control group were 3.05±1.11 and 2.13±0.63, and the joint fluid CXCL12 expression levels were 5.14±1.12 and 4.54±1.25. Therefore, the present results suggested that the expression levels of CXCR4 and CXCL12 in the RA-active group were significantly higher compared with the RA-remission (P<0.05) and control groups (P<0.05; Tables IV and V; Figs. 3 and 4).
 | Table IVCXCR4 expression levels in the serum and joint fluid of the active, remission, and control groups. |
| Table VCXCL12 expression levels in the serum and joint fluid of the active, remission and control groups. |
Correlations between CXCR4 and CXCL12 expression levels and ESR, CRP, RF and DAS28 scores
The expression levels of CXCR4 and CXCL12 had a positive correlation with the ESR, CRP, RF and DAS28 scores (data not shown) of patients with RA (P<0.05; Tables VI and VII; Figs. 5-8).
| Table VICorrelation between CXCR4 and CXCL12 expression in serum from the patients with RA and ESR, CRP, RF and DAS28 scores. |
| Table VIICorrelation between CXCR4 and CXCL12 expression in joint fluid from the patients with RA and ESR, CRP, RF and DAS28 scores. |
Correlation between the expression of CXCR4 and CXCL12 with disease activity
Compared with the RA-active group, the expression of CXCR4 and CXCL12 in the serum of the RA remission group was significantly lower. Therefore, the present results suggested that the expression levels of CXCR4 and CXCL12 were positively correlated with the changes in RA disease activity (CXCR4, r=0.858, P<0.001; CXCL12, r=0.864, P<0.001; Fig. 9).
Discussion
RA is a chronic systemic immune disease and its pathogenesis has yet to be elucidated, but abnormal immunity is considered to contribute to its development (26). Previous studies have demonstrated that over the course of RA, inflammatory cells migrate from peripheral blood to synovial tissues and secrete a variety of inflammatory factors, resulting in the destruction of the synovial membrane (27,28). Chemokines serve an important role in the infiltration and migration of inflammatory cells (29). CXCL12 is the only chemokine that binds to the receptor CXCR4(30). CXCL12 and CXCR4 promote the migration of monocytes and T lymphocytes, and serve an important role in the process of inflammation (31). Previous studies have indicated that the expression levels of CXCL12 in the synovial tissue and joint fluid of patients with RA was increased, and that CXCR4 expression was also significantly increased in T lymphocytes (32-34).
CXCL12 can promote the secretion of matrix metalloproteins (MMPs) via chondrocytes, including MMP-1 and MMP-13(35). CXCR4 receptor antagonists have been used to reduce the expression levels of MMP-1 and MMP-13 in synovial fluid in patients with RA (36). In addition, CXCL12 and CXCR4 can further induce injury of the articular cartilage by promoting MMP secretion (37). Previous studies have demonstrated that CXCL12 and CXCR4 are closely associated with synovial cell inflammation in patients with RA (17,38), but to the best of our knowledge, no previous reports have discussed the correlation between CXCL12 and CXCR4, or disease activity in patients with RA.
The present results suggested that the expression levels of CXCR4 and CXCL12 in the RA-active group were significantly higher compared with the RA-remission and control groups (P<0.05), but there was no significant difference between the latter two groups. Therefore, the present results indicated that the expression levels of CXCR4 and CXCL12 may be closely associated with RA pathogenesis. The correlations between CXCR4 and CXCL12 expression levels, and ESR, CRP, RF and DAS28 scores in patients with RA were also investigated. The present results suggested that CXCR4 and CXCL12 expression levels were strongly positively correlated with ESR, CRP, RF and DAS28 scores (P<0.05). Therefore, these results indicated that CXCR4 and CXCL12 expression levels exhibited an effect on the disease activity of patients with RA and may be used as an index to evaluate this activity.
Previous studies have revealed that when CXCR4 and CXCL12 expression levels were increased, chemotaxis and activating effects were induced in immune cells, which leads to overactivation of immune cells and the subsequent secretion of additional inflammatory factors and their corresponding antibodies (39-41). This effect may explain the results of the present study, in which the CXCR4 and CXCL12 expression levels of patients with RA were significantly increased. Previous studies have indicated that synovial fibroblasts in patients with RA may produce high levels of CXCL12 compared with patients with osteoarthritis (21,42). This is primarily due to the hypomethylation of DNA in synovial fibroblasts in patients with RA compared with patients with osteoarthritis, which may affect CXCL12 expression (43). The results from these previous studies are in line with the results of the present study. In addition, previous studies have indicated that high expression levels of CXCL12 in patients with RA are associated with a variety of pathogenic events, and that the expression of CXCL12 was positively correlated with the expression of CRP, which is consistent with results from the present study (44,45). Moreover, other studies have used immunohistochemistry scoring to study synovial tissues of patients with RA and revealed that CXCL12 expression level was significantly correlated with DAS28 scores, and that the expression levels of CXCL12 and CXCR4 were closely associated with disease activity and joint destruction (46,47). Previous studies indicated that CXCL12/CXCR4 expression were positively correlated with RF expression (48-50), which was consistent with the results of the present study.
In conclusion, the results of the present study suggested that CXCL12 and CXCR4 are highly expressed in patients with RA, and that these levels are positively correlated with the ESR, CRP, RF and DAS28 scores. Collectively, the results of the current study suggested that these factors may be used as indexes to evaluate disease activity in patients with RA.
However, there are some limitations to the present study. Firstly, the present results indicated that CXCL12 and CXCR4 expression levels were increased in patients with RA, but it is unknown whether the continuous increase of CXCL12 and CXCR4 expression levels were related to disease severity. Correlational analyses were conducted between the expression levels of CXCL12 and CXCR4, and the related indexes of disease activity, but further analysis was not performed. Secondly, a close relationship was revealed between CXCL12 and CXCR4 and inflammation in patients with RA, but the correlation between CXCL12 and CXCR4, and the expression of related inflammatory factors was not analyzed. Inflammatory factors serve an important role in the pathogenesis of RA and are important for the clinical evaluation of the prognosis of patients with RA (51). In addition, due to the random array method for sample selection and the limited sample size, there may be a certain deviation between the research group and the control group. The present study recruited patients with osteoarthritis as the control group, rather than healthy individuals, as it is possible to extract bone and joint fluid during the examination of patients with osteoarthritis but not healthy individuals. However, the patients with osteoarthritis did not have rheumatic diseases, thus the selection may result in some bias. Future studies will further increase the sample size and recruit a more suitable selection of individuals as controls.
Acknowledgements
Not applicable.
Funding
This work was supported by Scientific Research Project of Health Department of Hubei Province (grant no. JX6C-29).
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
LP and BW conceived the study and designed the experiments. NZ, JM and LH contributed to the data collection and performed the experiments. YY, ZZ and LW performed the data analysis and interpreted the results. LP and NZ wrote the manuscript. BW contributed to the critical revision of article. All authors read and approved the final manuscript.
Ethics approval and consent to participate
All patients and their families agreed to participate in the experiment and signed an informed consent agreement. This experiment was approved by the Hospital Ethics Committee of First People's Hospital of Jingzhou.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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