Foxc1 promotes the proliferation of fibroblast-like synoviocytes in rheumatoid arthritis via PI3K/AKT signalling pathway
Introduction
Rheumatoid Arthritis (RA) is a chronic and systemic disease which is characterized by recruitment of inflammatory cells and accumulation of cytokines, leading to infiltration by macrophages and T cell synovial lining hyperplasia, neo-angiogenesis, pannus formation and destruction of cartilage and bone (Henry et al., 2013). There are various cell types participating in the chronic inflammatory process of RA pathogenesis, including T cells, B cells, fibroblast-like synoviocytes (FLSs) and macrophages. Among them, the FLSs are the most important cells responsible for initiating and driving the inflammatory process as well as the invasive nature of the rheumatoid synovium (Feldmann et al., 1996). Recent studies have demonstrated that abnormal activation of FLSs in the RA inflammatory environment may have unique morphology and share many characteristics with tumour-like cells. These cells finally become insensitive to cell-cell contact inhibition and acquired enhanced migration, invasion and angiogenesis potentiality. FLSs, which were stimulated by RA inflammatory infiltration, were considered to be responsible for the abnormal proliferation and pathogenesis of RA (Zhu et al., 2011). More, FLSs promote chronic inflammation response through secretion of pro-inflammatory cytokines, chemokines and matrix degrading enzymes, such as TNF-α, IL-1β and MMPs. All these inflammation cytokines deeply maintain and enlarg the inflammatory and joint destruction in RA (Neumann et al., 2010). Although RA synoviocytes and those transformed cells are shared with the same characteristics, the pathogenesis of proliferation was still poor understood (Lee et al., 2014).
Forkhead boxc1 (FOXC1) is a member of Forkhead box family transcription factors which play important roles in multiple pathophysiological biological processes such as metabolism, differentiation, proliferation, apoptosis, migration, invasion and longevity (Nishimura et al., 1998). Previous studies have indicated that Foxc1 has participated in the development of various types of malignancy. For example, in nasopharyngeal carcinoma, the expression level of Foxc1 was enhanced, and Foxc1 plays a key role in epithelial–mesenchymal transition (EMT) with the upregulation of Vimentin, fibronectin and N-cadherin expression (Ou-Yang et al., 2015). Over-expression of Foxc1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma, non-small cell lung cancer and pancreatic ductal adenocarcinoma patients (Wang et al., 2013; Wei et al., 2013; Xia et al., 2013). Therefore, considering the fact that activated FLSs in the RA inflammatory environment may have unique morphology and share many characteristics with tumour-like cells (Lefevre et al., 2015), we hypothesized that Foxc1 may also play an important role in the RA inflammation process.
In this investigation, we confirmed the markedly upregulated expression of Foxc1 in the synovium of RA patients compared with healthy controls, as well as its co-localization with FLSs. Besides, the role of Foxc1 in the expression of inflammatory cytokines and MMPs in response to TNF-α treatment had also been further studied (Chang et al., 2014; Yamazaki et al., 2003). Furthermore, we also verified that Foxc1 could promote the proliferation of RA-FLSs via inactivation of PI3K/AKT signaling pathway. Taken together, our findings suggest that Foxc1 could be a useful therapeutic target in RA disease.
Section snippets
Patients and RASFs
Our cohort of RA patients included five females and five males. Samples were obtained from patients who underwent total knee replacement surgery. This study was conducted RA patients, fulfilling the 1987 American College of Rheumatology classification criteria for rheumatoid arthritis. In our current study, the Disease Activity Score (DAS) is the major scoring system for evaluating disease activity of rheumatoid arthritis (RA) and RA patients whose DAS score is higher than 3.2 were recruited in
Upregulation of Foxc1 expression in synovial tissue of RA patients
To investigate whether Foxc1 contributes to rheumatoid arthritis (RA) progression, representative examples of RA patients and healthy controls were shown in Fig. 1A. Compared with healthy control group, apparent hyperplasia of synovium was observed in RA tissue. To further validate the expression of Foxc1 in synovial tissue of RA patients and healthy control patients, we performed western blot analyses. As shown in Fig. 1B, the expression of Foxc1 protein was visibly increased in RA patients.
Discussion
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory hyperplasia of synovial tissue and joint destruction (McInnes and Schett, 2011; Scott et al., 2010). Fibroblast-like synoviocytes (FLSs) play a crucial role in synovial tissue hyperplasia. Previous studies have proved that activated RA-FLSs could produce various pro-inflammatory cytokines in synovial membrane (Capellino et al., 2014). A lot of inflammatory cytokines such as TNF-α and IL-6 could promote
Conflict of interest
None.
Acknowledgment
None.
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These authors contribute equally to this study.