Systemic Sclerosis Research Indicates Estrogen May Play Positive Role, Potentially Leading to Treatments

Researchers at Paris Descartes University, France, recently presented the results of a study investigating the effects of estrogen in the development of experimental dermal fibrosis and on the response of profibrotic cells to the major fibrosis cytokine-transforming growth factor (TGF)-β.

The presentation, “Estrogens Inhibit the Profibrotic Effects of TGF-Beta and Protect from the Development of Experimental Dermal Fibrosis,” took place last week at the 4^th Systemic Sclerosis World Congress in Lisbon, Portugal.

According to the American College of Rheumatology, systemic sclerosis, or scleroderma, is a relatively rare condition affecting 75,000 to 100,000 people in the U.S., mostly women. The most common age range when the condition develops is between 35 and 50, with postmenopausal women as the primary affected population.

Due to the clear sex bias in systemic sclerosis, researchers aimed to assess if estrogen, one of the female hormones that decreases in menopause, plays a role in the development or vulnerability to the disease. The team focused on two effects: the development of experimental dermal fibrosis, and the response of dermal fibroblasts to TGF-β, the master cytokine behind the development of fibrosis.

Using gene inactivation or targeted molecular strategies, the researchers evaluated the effect of estrogen inhibition in mice models of induced dermal fibrosis and tight skin. In addition, systemic sclerosis dermal fibroblasts were incubated with different concentrations of estradiol (a form of estrogen) and/or tamoxifen (a hormone therapy). In these cells, scientists measured collagen release, differentiation of fibroblasts into myofibroblasts, and activation of the TGF-β pathway, all processes involved in the onset of fibrosis and systemic sclerosis.

The results showed that, in both mice models, estrogen inhibition led to the activation of the TGF-β pathway and exacerbated skin fibrosis. In dermal fibroblasts, treatment with estradiol significantly decreased the stimulation of the TGF-β pathway on collagen synthesis and fibroblast differentiation into myofibroblasts. Tamoxifen, a drug that competes with estrogen, reversed the inhibitory effects of estrogen and restored the TGF-β pathway-induced collagen synthesis.

According to the abstract from the Systemic Sclerosis World Congress, the research team concluded: “Our results demonstrate a beneficial effect of estrogen in experimental dermal fibrosis. … These findings may contribute to the occurrence of [systemic sclerosis] in postmenopausal women and the greater severity of the disease in men, and open avenues to potential hormonal therapies.”