TY - JOUR
T1 - Activation of the estrogen receptor contributes to the progression of pulmonary lymphangioleiomyomatosis via matrix metalloproteinase-induced cell invasiveness
AU - Glassberg, Marilyn K.
AU - Elliot, Sharon J.
AU - Fritz, Jason
AU - Catanuto, Paola
AU - Potier, Mylene
AU - Donahue, Roger
AU - Stetler-Stevenson, William
AU - Karl, Michael
N1 - Funding Information:
M.K.G., J.F., and M.K. received research funding from the American Lung Association of Florida and The Macricostas Family Foundation, Inc., Deno and Marie Macricostas.
PY - 2008/5
Y1 - 2008/5
N2 - 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)-α and ERβ analyses were conducted by RT-PCR. ERα and ERβ, 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 (ERα and ERβ), which undergo rapid intracellular turn-over in their unbound state. 17β-Estradiol (E2) enhances the transcriptional ER activity. E2-induced ER activation increases synthesis and activity of MMP-2 through posttranscriptional mechanisms in LAMD-SM. The E2/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.
AB - 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)-α and ERβ analyses were conducted by RT-PCR. ERα and ERβ, 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 (ERα and ERβ), which undergo rapid intracellular turn-over in their unbound state. 17β-Estradiol (E2) enhances the transcriptional ER activity. E2-induced ER activation increases synthesis and activity of MMP-2 through posttranscriptional mechanisms in LAMD-SM. The E2/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.
UR - http://www.scopus.com/inward/record.url?scp=43249088754&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43249088754&partnerID=8YFLogxK
U2 - 10.1210/jc.2007-1283
DO - 10.1210/jc.2007-1283
M3 - Article
C2 - 18285421
AN - SCOPUS:43249088754
SN - 0021-972X
VL - 93
SP - 1625
EP - 1633
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 5
ER -