Estrogens Counteract the Profibrotic Effects of TGF-β and their Inhibition Exacerbates Experimental Dermal Fibrosis

Systemic sclerosis primarily affects women. This sex bias raises the question on the role female hormones could play in the development of fibrosis, which is largely unknown. Our aim was to evaluate the effects of estrogens in the development of experimental dermal fibrosis, in the mouse models of bleomycin-induced dermal fibrosis and tight skin (Tsk-1) mice, and on the activation of dermal fibroblasts by transforming growth factor-beta (TGF-beta). Estrogen inhibition, obtained through gene inactivation for the estrogen receptor-alpha knockout or treatment with tamoxifen, exacerbated skin fibrosis in the bleomycin model and in the Tsk-1 mice. In the dermal fibroblasts, treatment with 17-beta-estradiol significantly decreased the stimulatory effects of TGF-beta on collagen synthesis and myofibroblast differentiation, decreased the activation of canonical TGF-beta signaling, and markedly reduced the expression of the TGF-beta target genes. Tamoxifen reversed the inhibitory effects of estrogens by restoring Smad2/3 phosphorylation and TGF-beta-induced collagen synthesis. Our results demonstrate a beneficial effect of estrogens in dermal fibrosis. Estrogens reduce the TGF-bedependent activation of dermal fibroblasts, and estrogen inhibition leads to a more severe experimental dermal fibrosis. These findings are consistent with the prominent development of systemic sclerosis in postmenopausal women and the greater severity of the disease in men.