Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis
- Dawei Li†1Email author,
- Yuji Wang†1, 2Email author,
- Nanwei Xu2,
- Qianghua Wei3,
- Min Wu4,
- Xiaofeng Li5,
- Ping Zheng6,
- Sai Sun1,
- Yuli Jin3,
- Gailian Zhang5,
- Ruomin Liao7 and
- Ping Zhang8
© Li et al.; licensee BioMed Central Ltd. 2011
Received: 16 November 2010
Accepted: 8 February 2011
Published: 8 February 2011
Follistatin-like protein 1 (FSTL1) is a proinflammation mediator implicated in arthritis in rodent animal models. The present study is aimed at assessing FSTL1 levels in systemic autoimmune diseases and correlating them with disease activity in patients with rheumatoid arthritis (RA).
Serum FSTL1 levels from 487 patients with systemic autoimmune diseases and 69 healthy individuals were measured by enzyme-linked immunosorbent assay (ELISA). FSTL1 expression in synovial fluid (SF) and synovial tissues (STs) was determined by ELISA, immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and western blot analysis in RA patients and trauma controls. FSTL1 levels in fibroblast-like synoviocytes (FLSs) from RA patients were determined by real-time PCR and western blot analysis.
Serum FSTL1 levels were significantly elevated in patients with RA, ulcerative colitis, systemic lupus erythematosus, Sjögren's syndrome (SS), systemic sclerosis and polymyositis/dermatomyositis. Serum FSTL1 levels in the RA and secondary SS patients were substantially higher than those in other patients. Serum FSTL1 levels were increased in early RA, rheumatoid factor (RF)- and anti-cyclic citrullinated peptide antibody (ACPA)-negative patients compared to healthy controls. Moreover, serum FSTL1 concentrations were significantly higher in long-standing RA patients than in early RA patients and in the RF- and ACPA-positive RA patients than in RF- and ACPA-negative RA patients. Elevated FSTL1 levels in the STs and SF of RA patients were also observed. FSTL1 levels in serum were markedly higher than those in SF in RA patients. The strongest FSTL1 staining was detected in the cytoplasm of synovial and capillary endothelial cells from RA synovium. Furthermore, FSTL1 was induced in FLSs by inflammatory mediators. Importantly, serum FSTL1 levels were correlated with several important biologic and clinical markers of disease activity, including erythrocyte sedimentation rate, C-reactive protein, RF, ACPA, swollen joint count, patient global visual analogue scale score and Disease Activity Score 28 in the adult RA patient population. Notably, serum FSTL1 levels were significantly diminished following successful treatment and clinical improvement.
Elevated FSTL1 levels reflect not only joint diseases but also inflammation and tissue degradation in systemic autoimmune diseases. Serum FSTL1 levels may thus serve as a serological inflammatory marker of disease activity in RA patients.
Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein with extensive glycosylation modifications and exists in two isoforms that differ in the extent of sialylation . It is widely expressed in all organs  and is also detectable in the medium of cardiac myocytes  and endothelial cells (ECs) . FSTL1 expression is upregulated in cardiac and skeleton myocytes in response to ischemic stress  and in the osteoblast cell line stimulated with proinflammation cytokines . It has been shown that FSTL1 functions as an antiapoptotic protein by increasing both Akt and extracellular signal-regulated kinase activities . FSTL1 promotes EC function and stimulates revascularization through activation of the Akt-endothelial nitric oxide synthase signaling pathway . FSTL1 serum concentrations have been assessed in healthy individuals and in patients with acute coronary syndrome and were found to correlate with disease mortality during follow-up .
Rheumatoid arthritis (RA) is characterized by persistent multiple synovial inflammation and joint destruction. FSTL1 has also been reported to be involved in the pathogenesis of RA. Tanaka et al.  first identified it as an autoantigen when FSTL1 autoantibodies were found in the serum and synovial fluid (SF) of RA patients. Furthermore, FSTL1 mRNA is upregulated in the RA synovium  and the inflammatory synovial pannus of the collagen-induced arthritis (CIA) mouse . Recently, it has been demonstrated that FSTL1 is a novel proinflammatory molecule. Overexpression of FSTL1 in macrophages and fibroblasts augments the activity of proinflammatory cytokines, including interleukin (IL)-1β, tumor necrosis factor α (TNFα), and IL-6 and causes severe arthritis in the normal mouse . FSTL1 neutralization was shown to ameliorate arthritis by inhibiting production of interferon (IFN)-γ and chemokine (C-X-C motif) ligand 10 in arthritic joints of CIA mice . The aims of the present study were to determine FSTL1 levels in patients with systemic autoimmune diseases and to further assess the relationship between serum FSTL1 levels and RA disease progression.
Materials and methods
Characteristics and serum FSTL1 levels of the subjects investigateda
Total number of subjects
Number of female/male subjects
Disease durationb, years
Serum FSTL1 levels, μg/l
Lower 95% CI
Upper 95% CI
Above normal, %c
P versus HC
P versus RA
Disease characteristics of RA patients investigateda
Median (25th to 75th percentile)
33 (17 to 61)
8.1 (2.5 to 33.6)
63.6 (15 to 185.5)
251.9 (42.65 to 650.7)
Tender joint count
4 (2 to 7)
Swollen joint count
2 (1 to 5)
Patient global VAS score
50 (30 to 70)
4.7 (3.4 to 5.6)
Synovial tissues (STs) from another cohort of 14 RA patients (median age, 53 years; median disease duration, 6.5 years; median DAS28 score, 4.3) were obtained by total knee joint replacement or arthroscopic synovectomy. Each sample was inspected visually to ensure that only inflamed tissue was included. Control samples were taken from 13 trauma patients with normal synovium. Most of tissue samples were split into three parts: one was stored at -70°C for mRNA and protein extraction, one was fixed in 4% paraformaldehyde and embedded in paraffin and one was minced and used for separation of synovial cells immediately upon acquisition. SF was collected from most of these patients during knee joint surgery.
Collection of ST, SF and peripheral blood samples was performed according to the medical ethics regulations of Nanjing Medical University. This study was approved by the Nanjing Medical University Review Board, and written permission was requested and received from all patients and healthy individuals in the study.
Enzyme-linked immunosorbent assay
Serum FSTL1 levels were measured using a standard quantitative sandwich ELISA (Groundwork Biotechnology Diagnosticate, San Diego, CA, USA) with a 100 pg/ml detection limit of sensitivity. Serum and SF samples were diluted 1:5 and 1:10 in phosphate-buffered saline, respectively. Concentrations were reported as micrograms per liter. All analyses and calibrations were performed in duplicate. Optical densities were determined using an absorbance microplate reader (Elx808™ BioTek Instruments, Winooski, VT, USA) at 450 nm. Gen5 Data Analysis software (BioTek Instruments) was used to analyze all materials and depict the standard curve.
Total RNA was extracted from minced cryogenic tissues or cultured fibroblast-like synoviocytes (FLSs) using the miRNeasy Mini Kit (Qiagen, Basel, Switzerland) according to the manufacturer's instructions. On-column digestion of contaminated DNA was performed using the RNase-Free DNase Set (Qiagen). Total RNA (2 μg) was reverse-transcribed using the ReverTra Ace kit (Toyobo, Osaka, Japan) according to the manufacturer's instructions. A quantitative real-time polymerase chain reaction (RT-PCR) assay was performed using SYBR Green (Toyobo) in an Applied Biosystems 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA, USA). Primer sequences for amplifying FSTL1 cDNA and internal control glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were as follows: FSTL1, 5'-CGATGGACACTGCAAAGAGA-3' (forward) and 5'-CCAGCCATCTGGAATGATCT-3' (reverse); GAPDH, 5'-AGGGCTGCTTTTAACTCTGGT-3' (forward) and 5'-CCCCACTTGATTTTGGAGGGA-3' (reverse). The comparative threshold cycle method was used for relative quantification of mRNA.
Western blot analysis
Minced cryogenic tissues or cultured FLSs were lysed and boiled in sodium dodecyl sulfate (SDS) Lamini buffer. SDS-polyacrylamide gel electrophoresis was performed on 10% polyacrylamide gel and transferred to nitrocellulose membrane. Goat anti-human FSTL1 polyclonal antibody (R&D Systems, Minneapolis, MN, USA) and actin AC-40 (Sigma-Aldrich, St. Louis, MO, USA) were used to detect FSTL1 and β-actin expression, respectively.
Immunohistochemical staining with polyclonal anti-FSTL1 antibody was performed on archival formalin-fixed, paraffin-embedded ST using the peroxidase technique. Briefly, sections were deparaffinized and rehydrated. Epitope retrieval was performed in citrate buffer (pH 6) in a water bath at 98°C for 35 minutes with cooling for 20 minutes before immunostaining. Tissues were incubated with the primary anti-FSTL1 antibody (1:400 dilution) overnight at 4°C after blocking and then exposed to biotinylated secondary linking antibody (Boster, Wuhan, China) for 20 minutes. Biotin detection was performed with peroxidase-conjugated streptavidin. Finally, the slides were incubated with 3,3'-diaminobenzidine (Boster) for about 5 to 10 minutes and with hematoxylin as a counterstain for 1 minute. Sections were washed between incubations with Tris-buffered saline buffer (pH 7.6). Goat polyclonal antibody immunoglobulin G (IgG) was used as a negative control throughout. Each section was examined independently by two investigators (DL and YW) in a blinded manner.
Isolation and culture of human synovial fibroblasts
ST specimens were obtained from patients with RA or trauma by synovectomy or joint replacement surgery. These joint tissues were minced and incubated with 1 mg/ml collagenase I (Sigma-Aldrich, St. Louis, MO, USA) in serum-free Dulbecco's modified Eagle's medium (DMEM) (Gibco BRL, Grand Island, NY, USA) for 4 hours at 37°C, filtered through a nylon mesh, extensively washed and cultured in DMEM supplemented with 10% fetal calf serum (Gibco), 100 U of penicillin, 100 μg/ml streptomycin, and 2 mM L-glutamine in a humidified atmosphere containing 5% CO2. After overnight culture, the nonadherent cells were removed. The adherent cells were split at a ratio of 1:3 after these cells grew to 80% confluence. Synoviocytes were used from passages 4 through 6 in these experiments, during which they consisted of a homogeneous population of FLSs.
Reagents and stimulation assays
Cultured FLSs were grown in 100-mm cell culture dishes (6 to 8 × 105 cells/dish). Cultures were stimulated for 24 hours for mRNA extraction or for 36 hours for protein collection with the following agents: 20 μg/ml polyinosinic:polycytidylic acid (InvivoGen, San Diego, CA, USA), 100 ng/ml lipopolysaccharide from Escherichia coli (Sigma-Aldrich), 300 ng/ml bacterial lipoprotein (InvivoGen), 10 ng/ml recombinant interleukin-1β (IL-1β) (Invitrogen, Carlsbad, CA, USA), 10 ng/ml tumor necrosis factor α (TNFα) (Invitrogen) and 10 ng/ml transforming factor β (TGFβ) (Invitrogen).
Statistical analyses were performed using Prism and Instat software (GraphPad Software, San Diego, CA, USA) and SPSS 13.0 software (SPSS Inc., Chicago, IL, USA). The significance of the differences was evaluated using the Kruskal-Wallis test among multiple groups and the Mann-Whitney U test between groups. Follow-up data were evaluated by the Wilcoxon matched pairs test. The relationships between serum FSTL1 levels and other parameters were evaluated using Spearman's rank-correlation test. All quoted P values were two-tailed, and P values less than 0.05 were considered significant.
Serum FSTL1 levels that were not normally distributed were transformed to their natural logarithm (ln) for the regression analyses. Linear multiple regression analyses were performed with ln(FSTL1) levels as dependent variables and the raw data of CRP, ESR, RF, ACPA, disease duration, sex and age as independent variables. The test for significance of regression is carried out using the analysis of variance. The t-test was used to check the significance of individual regression coefficients in the multiple linear regression model. The level of significance was set at 0.05.
Serum FSTL1 levels in patients with systemic autoimmune diseases
Serum FSTL1 levels in the subgroups of RA patients
Elevated FSTL1 expression in ST and SF in patients with RA
Immunohistochemical localization of FSTL1 in STs in patients with RA
Increased FSTL1 expression in FLSs from RA patients induced by proinflammatory mediators
Serum FSTL1 levels correlated with parameters of disease activity in patients with RA
Independent association of FSTL1 with baseline characteristics in 198 RA patientsa
Disease duration, years
Effects of treatment on serum FSTL1 levels in patients with RA
In this study, we have found for the first time that serum FSTL1 levels are significantly elevated in patients with systemic autoimmune diseases, including RA, UC, SLE, SS, SSc and PM/DM. Furthermore, we have revealed that serum FSTL1 levels are correlated with serologic and clinical features of disease activity in the RA patient population. Finally, we have observed that serum FSTL1 levels are significantly decreased in RA patients following successful treatment and clinical improvement. These observations suggest that FSTL1 can serve as a reliable serological marker for disease activity in the RA patient population.
We also systemically assessed FSTL1 expression in adult RA patients for the first time. We found that FSTL1 levels were also increased in the STs and SF of RA patients. The strongest FSTL1 staining was detected in the cytoplasm of synovial and capillary ECs from RA synovium. Interestingly, we found that FSTL1 concentrations in serum were higher than those in synovial fluid in the adult RA population, suggesting that the source of FSTL1 was not limited to the synovium. In fact, previous reports have shown that FSTL1 is widely expressed in almost all organs, especially the lung and heart in rat . Moreover, FSTL1 is also referred as a "myokine" because it is secreted into the peripheral blood by cardiac and skeletal muscle [3, 4]. Oshima et al.  reported that FSTL1 is also secreted by ECs. Our results indicate that FSTL1 stained strongly in inflammatory ECs. These data suggest that ECs are a potential source of serum FSTL1, especially for those RA patients with complications such as rheumatoid vasculitis, pericarditis and pleuritis. However, we did observe that FSTL1 stained strongly in synovial cells and was induced in FLS by proinflammatory cytokines from RA patients. Therefore, we proposed that FLS is also the source of elevated FSTL1 levels, at least in STs. For these RA patients with lack of systemic arthritis symptoms, we could not exclude the possibility that FLS stimulated continually by proinflammatory mediators increased FSTL1 concentrations in STs and then released FSTL1 into serum.
A variety of autoantibodies exist, and microvascular EC injury frequently occurs among systemic autoimmune diseases, including RA, SLE, SS, SSc and PM/DM. It has been recognized that EC damage is caused by circulating immune complexes containing RF and other autoantibodies that form deposits in vessel walls, where they trigger an inflammatory reaction that leads to EC injury [21, 22]. Previous reports have shown that FSTL1 was secreted by ECs . In agreement with those observations, we found that FSTL1 stains strongly in inflammatory ECs. These findings raised the possibility that inflammatory ECs are responsible for high serum FSTL1 levels in those diseases. In addition, FSTL1 is also known to be secreted into the peripheral blood by cardiac and skeletal muscle, especially by ischemic muscle in a mouse model [3, 4]. Skeletal muscle inflammation and injury could also lead to higher serum FSTL1 levels in PM/DM. However, serum FSTL1 levels were not elevated in seronegative spondyloarthropathy, including AS, PsA and ReA, possibly because of less frequent autoantibody-mediated vascular injury and vasculitis. It remains to be seen whether elevated serum FSTL1 levels found in systemic autoimmune diseases are relevant to the autoimmune response underlying the disease process.
Serum FSTL1 levels in RA and sSS patients were substantially higher than those in other patients. In fact, the disease of most sSS patients was secondary to RA in the present study. This finding may be explained by both persistent synovitis of multiple joints and frequent extraarticular manifestations in RA patients. Increased serum FSTL1 levels could reflect not only chronic multiple synovial joint inflammation but also systemic inflammation and tissue degradation.
Although the effects of increased FSTL1 on the inflammation process were not assessed in this study, it has been recently reported that FSTL1 is a novel proinflammatory mediator in a rodent animal model [5, 10]. High circulating FSTL1 levels in RA patients might possibly cause deterioration in patients with arthritis by promoting production of proinflammatory cytokines and chemokines in arthritic joints. Another possibility is that FSTL1 promotes arthritis by increasing neovascularization of inflammatory synovium. It has been established that angiogenesis is associated with increased synovial inflammation and pannus formation and that blocking angiogenesis suppresses arthritis [23, 24]. Previous studies have shown that FSTL1 overexpression enhances revascularization in mouse ischemic limbs . Therefore, increased FSTL1 levels in RA could aggravate arthritis by FSTL1-mediated neovascularization in RA STs. However, some other reports have shown that FSTL1 plays immunosuppressive and immunomodulatory roles on immunity and inflammation. FSTL1 plays an immunomodulatory role in heart allograft transplantation  and ameliorates arthritis in mouse models [26, 27]. More recently, Adams et al.  reported that FSTL1 protected the kidney from acute nephrotoxic injury by inhibiting IL-1β expression. Therefore, it could be that FSTL1 plays different roles in varied cell and disease settings or at different stages in the pathogenesis and progression of arthritis. It remains to be determined whether different serum and tissue FSTL1 levels play different roles in the adult RA population. However, our findings that elevated serum FSTL1 levels and their correlations with inflammatory status in patients with RA suggest its proinflammatory effects, at least in the adult RA population.
Our data also reveal that serum FSTL1 levels correlate with several important biologic and clinical markers of disease activity, including ESR, CRP, swollen joint count, patient global VAS and DAS28 score in the RA population. Importantly, serum FSTL1 levels decreased markedly following clinical improvement. These data indicate that serum FSTL1 could serve as a new biomarker for disease activity in RA patients. A recent report has shown that serum FSTL1 levels are slightly elevated in systemic onset juvenile rheumatoid arthritis. However, it is premature to conclude that FSTL1 represents a biomarker for the disease, because only small samples with little clinical information were assessed in that recent study .
In comparison to the existing markers, such as ESR and CRP, serum FSTL1 was produced, at least partially, at local inflammation sites, including arthritic joints and blood vessels, which could reflect the status of tissue damage more accurately than those traditional markers. In addition, it has been observed in the clinic that some patients have normal or low levels of ESR or CRP despite extensive arthritis . Serum FSTL1 levels in these patients could be a useful inflammatory marker. Serum FSTL1 levels were independently related to titers of RF and ACPA, supporting the hypothesis that FSTL1 could be induced by immune complex-mediated vascular and tissue damage. In addition, RF and ACPA are correlated with a worse prognosis and the presence of aggressive disease . Further study is required to assess the relationship between serum FSTL1 levels and joint damage and radiological progression in the RA patient population.
FSTL1 levels are increased in systemic autoimmune diseases. Serum FSTL1 levels reflect the inflammatory status in RA patients. These results suggest that FSTL1 may serve as a novel biomarker for RA disease activity, raising the possibility that FSTL1 levels may be potential therapeutic targets in these diseases.
anti-cyclic citrullinated peptide antibodies
Disease Activity Score using 28 joint counts
disease-modifying antirheumatic drugs
enzyme-linked immunosorbent assay
follistatin-like protein 1
systemic lupus erythematosus
transforming factor β
tumor necrosis factor α
visual analog scale.
We thank Dr. Jun O. Liu (Pharmacology and Molecular Sciences, Johns Hopkins University, Baltimore, MD, USA) and Dr. Xianju Zhou (Department of physiology, Michigan State University, East Lansing, MI, USA) for valuable suggestions and critical comments on our manuscript. We thank Zhiqin Lv and Jing Luo (Department of Rheumatology, the Second Hospital, Shanxi Medical University, Taiyuan, Shanxi, P.R. China) and Hongwei Fu (Department of Rheumatology, Shanghai Jiaotong University, Shanghai, P.R. China) for providing help during our sample collection. This research was partially supported by China Postdoctoral Science Foundation grant 20090460590 to YW.
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