These authors contributed equally to this work.
Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells
Article first published online: 5 AUG 2011
© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society
British Journal of Pharmacology
Volume 164, Issue 1, pages 83–92, September 2011
How to Cite
Moir, L., Ng, H., Poniris, M., Santa, T., Burgess, J., Oliver, B., Krymskaya, V. and Black, J. (2011), Doxycycline inhibits matrix metalloproteinase-2 secretion from TSC2-null mouse embryonic fibroblasts and lymphangioleiomyomatosis cells. British Journal of Pharmacology, 164: 83–92. doi: 10.1111/j.1476-5381.2011.01344.x
- Issue published online: 5 AUG 2011
- Article first published online: 5 AUG 2011
- Accepted manuscript online: 21 MAR 2011 01:27PM EST
- Received; 24 September 2010; Revised; 21 January 2011; Accepted; 25 January 2011
- pulmonary lymphangioleiomyomatosis;
- matrix metalloproteinase;
- tissue inhibitors of matrix metalloproteinase
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.