Estrogen Blocks Profibrotic Signals Driving Scleroderma, Study Suggests

Blocking the activity of estrogen may worsen skin fibrosis in people with scleroderma, according to a study in mice.

Researchers from the Paris Descartes University, in France, believe that a lack of estrogen’s beneficial effects may help explain why scleroderma more commonly affects women after menopause — when the levels of this hormone decrease — and is often more aggressive in men.

The study, “Estrogens counteract the profibrotic effects of TGF-β and their inhibition exacerbates experimental dermal fibrosis,” was published in the Journal of Investigative Dermatology.

Scleroderma is characterized by the uncontrolled production of collagen by specialized pro-inflammatory cells called fibroblasts.

Collagen is a major protein in connective tissue, where it is required within the extracellular matrix to sustain the normal structure of cells. However, overproduction of collagen and other proteins can compromise tissue function, increase its stiffness, and induce fibrosis, or scarring.

Scleroderma is six times more frequent in women compared to men. However, data from the European Scleroderma Trial and Research (EUSTAR) group revealed that men have more severe disease manifestations and worse prognosis. Still, the underlying molecular mechanisms involved in this sex difference remain poorly understood.

Now, researchers used mouse models of scleroderma to explore the impact of the female hormone estrogen in the progression of fibrosis.

In one mouse model lacking a specific estrogen receptor, a compound called bleomycin was used to induce inflammation and fibrosis. In these animals, researchers found 36% more fibroblasts infiltrated in the skin, and an 87% thicker skin, compared with healthy animals. When compared with healthy animals also treated with bleomycin, the increase in skin thickness was 21%.

Further, in line with prior results from the same team, data showed that when mice models of scleroderma were given tamoxifen — which competes with estrogen and is used to treat breast cancer (brand names Nolvadex and Soltamox) — skin thickening increased by 28%, collagen accumulation was 23% higher, and the proportion of activated fibroblasts in the skin was 22% greater.

In a model of the later and less inflammatory stages of the disease, treatment with tamoxifen increased skin thickening by 31%, and led to an accumulation of 541% more hydroxyproline — a component of collagen — compared with controls. This suggested enhanced fibrosis.

Further experiments in skin fibroblasts revealed that 17-beta-estradiol, an active form of estrogen, significantly eased the effects of TGF-beta, a main driver of fibrosis, including its stimulation of collagen synthesis. In contrast, treatment with tamoxifen reversed the protective effects of estrogens.

“Our results demonstrate a beneficial effect of estrogens in dermal fibrosis,” the researchers said.

These findings are “consistent with the prominent occurrence of [scleroderma] in postmenopausal women, and the greater severity of the disease in men,” they added.