Doxycycline inhibits matrix metalloproteinase‐2 secretion from TSC2‐null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells

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 a...

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Veröffentlicht in:	British journal of pharmacology Jg. 164; H. 1; S. 83 - 92
Hauptverfasser:	Moir, LM, Ng, HY, Poniris, MH, Santa, T, Burgess, JK, Oliver, BGG, Krymskaya, VP, Black, JL
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	Oxford, UK Blackwell Publishing Ltd 01.09.2011 Nature Publishing Group
Schlagworte:	Animals Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Biological and medical sciences Cell Proliferation - drug effects Cells, Cultured doxycycline Doxycycline - pharmacology Female Fibroblasts Fibroblasts - cytology Fibroblasts - drug effects Fibroblasts - enzymology Fibroblasts - metabolism Humans Lymphangioleiomyomatosis - drug therapy Lymphangioleiomyomatosis - metabolism Lymphangioleiomyomatosis - pathology matrix metalloproteinase Matrix Metalloproteinase 2 - biosynthesis Matrix Metalloproteinase 2 - secretion Matrix Metalloproteinase Inhibitors Medical sciences Metabolism Mice Middle Aged Mitochondria - drug effects Myocytes, Smooth Muscle - metabolism Pharmacology. Drug treatments proliferation pulmonary lymphangioleiomyomatosis Research Papers Rodents Smooth muscle Tissue Inhibitor of Metalloproteinase-1 - metabolism Tissue Inhibitor of Metalloproteinase-2 - metabolism tissue inhibitors of matrix metalloproteinase Tumor Cells, Cultured Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - metabolism Cell proliferation Embryo Lung Metalloendopeptidases Respiratory system tissue inhibitors of matrix metalloproteinase Protein synthesis inhibitor proliferation Enzyme Secretion Tetracycline derivatives Rodentia pulmonary lymphangioleiomyomatosis In vitro Gelatinase A Peptidases Vertebrata Antibiotic Mammalia Mouse Animal Doxycycline Hydrolases matrix metalloproteinase Antibacterial agent Fibroblast
ISSN:	0007-1188, 1476-5381, 1476-5381
Online-Zugang:	Volltext
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Zusammenfassung:	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.
Bibliographie:	These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Article-2 ObjectType-Feature-1 content type line 23
ISSN:	0007-1188 1476-5381 1476-5381
DOI:	10.1111/j.1476-5381.2011.01344.x