Retinoic acids exhibit anti-fibrotic activity through the inhibition of 5-lipoxygenase expression in scleroderma fibroblasts
Posted Sep 17 2010 12:00am
The pathogenesis of systemic sclerosis (SSc) is not fully understood and there is no effective treatment for this disease. Retinoic acid (RA) can modulate connective tissue metabolism, exhibit anti-fibrotic activity, and improve the clinical symptoms of SSc. However, the mechanisms by which RA elicits its anti-fibrotic actions remain to be determined.
The aim of this study was to elucidate the underlying mechanisms by which RA exerts beneficial effects on scleroderma . Cultured skin fibroblasts from patients with scleroderma were treated with RA and their effect on the expression of 5-lipoxygenase (LOX), transforming growth factor (TGF)-β1, connective tissue growth factor (CTGF), type I and type III collagen was tested by reverse transcription polymerase chain reaction (RT–PCR) and western immunoblotting.
The effect of MK886, a 5-LOX-specific inhibitor, on the expression of TGF-β1, CTGF, type I and type III collagen was also examined by RT–PCR. In cultured scleroderma fibroblasts, the expression of 5-LOX was elevated compared with normal human dermal fibroblasts. RA significantly inhibited the expression of 5-LOX and of TGF-β1, CTGF, type I and type III collagen.
We further found that the expression of TGF-β1, CTGF and type I and type III collagen mRNA was inhibited by MK886 in scleroderma fibroblasts. In vitro, RA reduced 5-LOX expression in scleroderma fibroblasts and downregulated TGF-β1 and CTGF expression, leading to the inhibition of type I and type III collagen synthesis.
Our results indicate that the clinical effects of RA on scleroderma are, at least in part, attributable to the reduction of 5-LOX expression and the subsequent suppression of TGF-β1 and CTGF expression that results in the blockade of collagenogenesis.