Activation of the Estrogen Receptor Contributes to the Progression of Pulmonary Lymphangioleiomyomatosis via Matrix Metalloproteinase-Induced Cell Invasiveness
The Journal of Clinical Endocrinology & Metabolism. 2008-05-01; 93(5): 1625-1633
DOI: 10.1210/jc.2007-1283
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1. 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.
Glassberg MK(1), Elliot SJ, Fritz J, Catanuto P, Potier M, Donahue R,
Stetler-Stevenson W, Karl M.
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.
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.
DOI: 10.1210/jc.2007-1283
PMID: 18285421 [Indexed for MEDLINE]