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J Clin Endocrinol Metab. 2008 May;93(5):1625-33. doi: 10.1210/jc.2007-1283. Epub 2008 Feb 19.

Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinase-induced cell invasiveness.

Author information

1
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Miami Miller School of Medicine, 1600 N.W. 10th Avenue, Miami, FL 33136, USA. mglassbe@med.miami.edu

Abstract

CONTEXT:

The role of estrogens in the pathogenesis of lymphangioleiomyomatosis (LAM), an aggressive and destructive, eventually fatal lung disease of women, is poorly understood.

OBJECTIVE:

The study was conducted to test the hypothesis that the lung disease in LAM is estrogen mediated and to determine whether estrogens contribute to the invasiveness of LAM.

DESIGN:

In vitro cell culture of spindle-shaped LAM cells (LAMD-SM) were isolated and propagated from affected lungs. Estrogen receptor (ER)-alpha and ERbeta analyses were conducted by RT-PCR. ERalpha and ERbeta, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinases (MMP)-2 had Western blot analysis for protein assessment. Activity assays were performed for MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase-2. Assessment of MMP-2 promoter function was done via transfection assays. Cell invasion chambers were used to determine and quantitate cell invasiveness.

SETTING:

The study was conducted at an academic medical center.

PATIENTS:

Tissue and cells were obtained from patients as outlined in approved institution review board protocol (97/007).

INTERVENTION:

LAMD-SM cells were treated with a specific MMP-2 antibody or a nonspecific inhibitor, doxycycline.

MAIN OUTCOME MEASURES:

Activity of MMP-2 and invasiveness of LAMD-SM cells were measured.

RESULTS:

LAMD-SM cells express functional ERs (ERalpha and ERbeta), which undergo rapid intracellular turnover in their unbound state. 17beta-estradiol (E(2)) enhances the transcriptional ER activity. E(2)-induced ER activation increases synthesis and activity of MMP-2 through posttranscriptional mechanisms in LAMD-SM. The E(2)/ER-mediated increase of MMP-2 promotes LAMD-SM invasiveness, in assays in vitro, which can be inhibited by specific antibodies against MMP-2 or doxycycline, an inhibitor of MMPs.

CONCLUSION:

The invasion and destruction of lung parenchyma in LAM is, at least partially, an estrogen-MMP-driven process, which has major implications for therapeutic interventions.

PMID:
18285421
DOI:
10.1210/jc.2007-1283
[Indexed for MEDLINE]

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