Genistein Inhibit Cytokines or Growth Factor-Induced Proliferation and Transformation Phenotype in Fibroblast-Like Synoviocytes of Rheumatoid Arthritis

Abstract

The purpose of this research is to study the effect of genistein on cytokines or growth factor-induced proliferation and transformation phenotype of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS). RA-FLS were primarily cultured. With respective stimulation of IL-1β, TNF-α, and EGF, genistein was applied to elucidate its effect on synoviocytes' growth number, cell proliferation assay, cell cycle using cell counts, (3)H-TdR incorporation and flow cytometry, the colony numbers under anchorage-independent condition, and the expression of MMP-2 and MMP-9 in synovial fibroblasts. EGF, IL-1β, and TNF-α increased (3)H incorporation in RA-FLS, respectively. EGF augmented clone numbers of RA-FLS under anchorage-independent condition and not IL-1β and TNF-α. Genistein had an inhibitory role on cell number and (3)H-TdR incorporation of RA-FLS stimulated with IL-1β, TNF-α and EGF; genistein arrested the cell cycle at G(1) restriction point; genistein decreased colony numbers under anchorage-independent condition stimulated by EGF in serum condition. IL-1β or TNF-α increased expression of MMP-9 and MMP-2 in rheumatoid synoviocytes; EGF stimulated expression of MMP-9 but not of MMP-2; genistein suppressed production of MMP-9 more than MMP-2 induced by IL-1β or TNF-α; rMMP-9, rMMP-2, or their inhibitors had no effect on the (3)H-TdR incorporation of synovial cells. Erk1/2 inhibitor (PD098 059) had obvious inhibitory effect on the (3)H incorporation induced by TNF-α or IL-1β; inhibitors of JNK (SP600 125) had no significant effect on the (3)H incorporation. While pretreatment with PD098059 had no marked inhibitory effect on MMP-9 expression induced by TNF-α or IL-1β, SP600125 decreased significantly the MMP-9 expression induced by TNF-α or IL-1β. Neither PD098059 nor SP600 125 could inhibit the MMP-2 expression induced by TNF-α or IL-1β. Genistein inhibited IL-1β, TNF-α or EGF-induced proliferation and MMP-9 expression in fibroblast-like synoviocytes of rheumatoid arthritis; the proliferation of RA-FLS was mediated by Erk1/2 but not JNK activation, while JNK activation was involved in the signal transduction pathway leading to MMP-9 expression in rheumatoid synoviocytes.

The therapeutic potential of plant flavonoids on rheumatoid arthritis

“…Li et al, 2013). Synovial hyperplasia, inflammatory cell infiltration, vascular proliferation, and bone or cartilage loss were attenuated in 7,3'-dimethoxyhesperetin treated AIA rats (Li et al, 2012).…”

“…Administration of 7,3'-dimethoxyhesperetin ( Figure 4, Structure 2) reduced paw edema and arthritis scores in AIA rats (Li et al, 2012;R. Li et al, 2013).…”

“…Enhanced synovial cell growth, induced by IL-1 and TNF-, was reduced with genistein treatment in vitro (Zhang et al 2012). Luteolin (3',4',5,7-tetrahydroxylflavone) (Figure 4) improved clinical scores, paw edema, the severity of arthritis and weight loss in AIA rats and CIA mice (Zhang et al 2012;Shi et al 2015); this effect was synergistic with palmitoylethanolamide, an endogenous fatty acid amide. Additionally radiological and histopathological changes in CIA were improved with luteolin/palmitoylethanolamide compared to monotherapy with either agent.…”

“…In another study, serum levels of IL-1 and TNF-protein were reduced in AIA rats treated with 7, 3'-dimethoxyhesperetin. Moreover, hesperetin significantly reduced the production of MMP-3 and IL-6 in human synovial cells stimulated with IL-1 (Choi and Li 2010; Li et al 2012;Li et al 2013). …”

“…In vitro proliferation of RA-FLS, stimulated by IL-1was attenuated with baicalein treatment (Chen et al 2013). Genistein inhibited proliferation of RA-FLS and induction of MMP-2 and MMP-9 in these cells, mediated by IL-1 or TNF-in vitro (Zhang et al 2012). …”