Background/Purpose:  Fibroblast-like synoviocytes (FLSs) contribute to synovial hyperplasia in rheumatoid arthritis (RA). Fibroblast growth factor 4 (FGF4) is a potent mitogen for tumor cells. The aim of our study was to investigate the expression of FGF4 in RA patients and its role in RA synoviocyte proliferation. Furthermore, the underlying pathways such as PI3K/Akt, p38-MAPK, and Erk-MAPK pathways were investigated to understand the potential mechanism of FGF4 in the pathogenesis of synovial hyperplasia.

Methods:  The serum level of FGF4 were detected by protein arrays in 20 disease modifying antirheumatic drugs (DMARDs) naïve RA patients and in 20 age- and sex- matched healthy controls. The mRNA expression levels of FGF4 in PBMCs isolated from 50 patients with RA, and 50 healthy controls mathed with age and gender were analyzed by real-time PCR. FLSs were isolated from RA synovium, and were co-cultured with different concentrations of recombinant human FGF­4 (rhFGF4) for 48 hours. Cell proliferation was quantified by Cell Counting Kit-8 assay and cell cycle distribution were evaluated by flow cytometry. Expression of cell cycle-related proteins were measured by western blot. Western blot analysis was also performed to determined the activation of PI3K/Akt, p38-MAPK, and Erk-MAPK pathways in RA-FLS after being treated with 50 ng/ml rhFGF4.

Results:  The serum expression of FGF4 in RA group was higher than that in control group (P<0.05). The FGF4 mRNA was highly expressed in PBMCs of RA, compared with the control group (P<0.05). RA-FLS treated with different concentrations of rhFGF4 (12.5, 25, 50, 100 and 200 ng/ml) showed significantly increased proliferation，with cell proliferation rates of (1.21±0.08), (1.26±0.12), (1.29±0.12), (1.34±0.14), (1.39±0.13), compared with that of controls (1.00±0.00) (P<0.05). Incubation with various concentrations of rhFGF4 (25, 50, 100 ng/ml) resulted in a significant increase of G₂/M+S phase cells compared to controls (P<0.05). And the protein expression of cyclin D1 was also up-regulated after being treated with rhFGF4 (P<0.05). The protein expression of p-Akt, p-p38 and p-Erk was significantly increased in RA-FLS after a 5 min exposure to rhFGF4, compared with the control group.

Conclusion:  Our results suggest that FGF4 is highly expressed in serum and in PBMCs of active RA patients. The proliferation of RA-FLS and the cell cycle G₁/S transition were promoted by rhFGF4. And cyclin D1 was up-regulated by treating with rhFGF4, indicating the aberrant activation of FGF4 may play a role in RA-FLS proliferation, contributing to synovial hyperplasia. It is possible that rhFGF4 promotes the proliferation of RA-FLS via activation of PI3K/Akt, p38-MAPK and Erk-MAPK signaling pathways.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effect-of-fibroblast-growth-factor-4-on-the-proliferation-of-fibroblast-like-synoviocytes-in-rheumatoid-arthritis/