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Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis.

Aida-Yasuoka K, Peoples C, Yasuoka H, Hershberger P, Thiel K, Cauley JA, Medsger TA, Feghali-Bostwick CA - Arthritis Res. Ther. (2013)

Bottom Line: We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model.Propyl-pyrazole-triol, but not genistein, significantly increased FN expression.The effects of E2 were abrogated by ICI 182,780.

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ABSTRACT

Introduction: Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17β-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls.

Methods: Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERβ selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry.

Results: E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc.

Conclusion: Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.

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Estradiol and estrone levels are increased in serum of patients with diffuse cutaneous systemic sclerosis. Dot plots of serum levels of estradiol and estrone in patients with diffuse cutaneous systemic sclerosis (SSc) and healthy controls. Measurements were made using 68 patients with SSc and 35 healthy controls. Differences in estradiol levels were not significant whereas estrone levels were statistically significant (P = 0.002).
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Figure 5: Estradiol and estrone levels are increased in serum of patients with diffuse cutaneous systemic sclerosis. Dot plots of serum levels of estradiol and estrone in patients with diffuse cutaneous systemic sclerosis (SSc) and healthy controls. Measurements were made using 68 patients with SSc and 35 healthy controls. Differences in estradiol levels were not significant whereas estrone levels were statistically significant (P = 0.002).

Mentions: Patient and control E2 serum samples were divided into low (<5 pg/ml), intermediate (5 to 10 pg/ml), and high (>10 pg/ml) levels (Table 1). Similarly, patient and control estrone serum samples were divided into low (<15 pg/ml), intermediate (15 to 75 pg/ml), and high (>75 pg/ml) levels (Table 1). There was a significant difference between SSc patient and control E2 and estrone levels (P = 0.04 and P = 0.006, respectively). The frequency of the data points is shown in the dot plots of Figure 5. Levels of E2 and estrone were also analyzed by disease specific clinical manifestations occurring at any time during the illness. Although the associations did not reach statistical significance, a larger proportion of patients with high estrone levels (42%) had gastrointestinal involvement compared with those patients with low estrone levels (17%, P = 0.07).


Estradiol promotes the development of a fibrotic phenotype and is increased in the serum of patients with systemic sclerosis.

Aida-Yasuoka K, Peoples C, Yasuoka H, Hershberger P, Thiel K, Cauley JA, Medsger TA, Feghali-Bostwick CA - Arthritis Res. Ther. (2013)

Estradiol and estrone levels are increased in serum of patients with diffuse cutaneous systemic sclerosis. Dot plots of serum levels of estradiol and estrone in patients with diffuse cutaneous systemic sclerosis (SSc) and healthy controls. Measurements were made using 68 patients with SSc and 35 healthy controls. Differences in estradiol levels were not significant whereas estrone levels were statistically significant (P = 0.002).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672719&req=5

Figure 5: Estradiol and estrone levels are increased in serum of patients with diffuse cutaneous systemic sclerosis. Dot plots of serum levels of estradiol and estrone in patients with diffuse cutaneous systemic sclerosis (SSc) and healthy controls. Measurements were made using 68 patients with SSc and 35 healthy controls. Differences in estradiol levels were not significant whereas estrone levels were statistically significant (P = 0.002).
Mentions: Patient and control E2 serum samples were divided into low (<5 pg/ml), intermediate (5 to 10 pg/ml), and high (>10 pg/ml) levels (Table 1). Similarly, patient and control estrone serum samples were divided into low (<15 pg/ml), intermediate (15 to 75 pg/ml), and high (>75 pg/ml) levels (Table 1). There was a significant difference between SSc patient and control E2 and estrone levels (P = 0.04 and P = 0.006, respectively). The frequency of the data points is shown in the dot plots of Figure 5. Levels of E2 and estrone were also analyzed by disease specific clinical manifestations occurring at any time during the illness. Although the associations did not reach statistical significance, a larger proportion of patients with high estrone levels (42%) had gastrointestinal involvement compared with those patients with low estrone levels (17%, P = 0.07).

Bottom Line: We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model.Propyl-pyrazole-triol, but not genistein, significantly increased FN expression.The effects of E2 were abrogated by ICI 182,780.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17β-estradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls.

Methods: Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERα specific ligand, and genistein, an ERβ selective ligand, to identify the signaling pathways mediating E2's effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry.

Results: E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc.

Conclusion: Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.

Show MeSH
Related in: MedlinePlus