Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis

Arthritis Research & Therapy, Feb 2011

Introduction 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). Methods 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. Results 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. Conclusions 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.

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Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis

Dawei Li 0 Yuji Wang 0 Nanwei Xu Qianghua Wei Min Wu Xiaofeng Li Ping Zheng Sai Sun 0 Yuli Jin Gailian Zhang Ruomin Liao Ping Zhang 0 State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Sciences, Fudan University , 220 Handan Road, Shanghai, 200433 , People's Republic of China Introduction: 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). Methods: 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. Results: Serum FSTL1 levels were significantly elevated in patients with RA, ulcerative colitis, systemic lupus erythematosus, Sjgren'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 longstanding RA patients than in early RA patients and in the RF- and ACPA-positive RA patients than in RF- and ACPAnegative 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. Conclusions: 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. - Introduction 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 [1]. It is widely expressed in all organs [2] and is also detectable in the medium of cardiac myocytes [3] and endothelial cells (ECs) [4]. FSTL1 expression is upregulated in cardiac and skeleton myocytes in response to ischemic stress [4] and in the osteoblast cell line stimulated with proinflammation cytokines [5]. It has been shown that FSTL1 functions as an antiapoptotic protein by increasing both Akt and extracellular signal-regulated kinase activities [3]. FSTL1 promotes EC function and stimulates revascularization through activation of the Akt-endothelial nitric oxide synthase signaling pathway [4]. 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 [6]. 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. [7] 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 [8] and the inflammatory synovial pannus of the collagen-induced arthritis (CIA) mouse [9]. 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)1b, tumor necrosis factor a (TNFa), and IL-6 and causes severe arthritis in the normal mouse [10]. FSTL1 neutralization was shown to ameliorate arthritis by inhibiting production of interferon (IFN)-g and chemokine (C-X-C motif) ligand 10 in arthritic joints of CIA mice [5]. 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 (...truncated)


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Dawei Li, Yuji Wang, Nanwei Xu, Qianghua Wei, Min Wu, Xiaofeng Li, Ping Zheng, Sai Sun, Yuli Jin, Gailian Zhang, Ruomin Liao, Ping Zhang. Follistatin-like protein 1 is elevated in systemic autoimmune diseases and correlated with disease activity in patients with rheumatoid arthritis, Arthritis Research & Therapy, 2011, pp. R17, 13, DOI: 10.1186/ar3241