Document Detail


Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells.
MedLine Citation:
PMID:  21418186     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Lymphangioleiomyomatosis (LAM) is characterized by the abnormal growth of smooth muscle-like cells (LAM cells) and cystic destruction of the lung parenchyma. LAM cell-derived matrix metalloproteinases (MMPs) are thought to play a prominent role in the tissue destruction. The aim of this study was to determine whether doxycycline, a known MMP inhibitor, can inhibit LAM cell proliferation or mitochondrial function and/or modulate MMPs and their tissue inhibitors (TIMPs).
EXPERIMENTAL APPROACH: Wild-type and tuberous sclerosis complex-2 (TSC2)-null mouse embryonic fibroblasts (MEFs) were cultured in DMEM containing 10% fetal bovine serum (FBS). Human LAM cells were derived from the lungs of LAM patients and airway smooth muscle cells from control subjects. Cells were stimulated with FBS with or without doxycycline for up to 9 days. Proliferation was assessed by manual cell counts and MTT assay, MMP production by zymography and ELISA, and TIMP production using elisa.
KEY RESULTS: Doxycycline did not change FBS-induced proliferation in MEFs or human cells. However, doxycycline did reduce metabolic activity of both wild-type and TSC2-null MEFs and LAM cells, but had no effect on control cells. Furthermore, doxycycline reduced MMP-2 from MEFs and decreased active-MMP-2 from LAM cells but had no effect on TIMP-1 and TIMP-2 from human LAM cells.
CONCLUSIONS AND IMPLICATIONS: Doxycycline decreased MMP levels and cell metabolic activity, which raises the possibility of therapeutic efficacy in LAM.
Authors:
L M Moir; H Y Ng; M H Poniris; T Santa; J K Burgess; B G G Oliver; V P Krymskaya; J L Black
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  164     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-08     Completed Date:  2012-02-02     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  83-92     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Affiliation:
Woolcock Institute of Medical Research, Sydney, NSW, Australia. lyn.moir@sydney.edu.au
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Proliferation / drug effects
Cells, Cultured
Doxycycline / pharmacology*
Female
Fibroblasts / cytology,  drug effects,  enzymology,  metabolism
Humans
Lymphangioleiomyomatosis / drug therapy*,  metabolism*,  pathology
Matrix Metalloproteinase 2 / biosynthesis,  secretion
Matrix Metalloproteinase Inhibitors*
Mice
Middle Aged
Mitochondria / drug effects
Myocytes, Smooth Muscle / metabolism
Tissue Inhibitor of Metalloproteinase-1 / metabolism
Tissue Inhibitor of Metalloproteinase-2 / metabolism
Tumor Cells, Cultured
Tumor Suppressor Proteins / deficiency*,  metabolism
Grant Support
ID/Acronym/Agency:
R01 HL090829/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Matrix Metalloproteinase Inhibitors; 0/Tissue Inhibitor of Metalloproteinase-1; 0/Tumor Suppressor Proteins; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 4JG2LF96VF/tuberous sclerosis complex 2 protein; 564-25-0/Doxycycline; EC 3.4.24.24/Matrix Metalloproteinase 2
Comments/Corrections

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