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1.
Cytokine ; 46(3): 332-8, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19342253

ABSTRACT

Cartilage degradation is mediated by matrix metalloproteinases (MMPs) and their inhibitors, tissue metalloproteinases (TIMPs), which are transcriptionally regulated by a variety of growth factors and cytokines. The levels of various MMPs as well as TIMPs have been shown to increase in response to certain cytokines. These include leukaemia inhibitory factor (LIF) and Oncostatin M (OSM), both of which have been detected in the synovial fluids of patients with rheumatoid arthritis (RA). However, the role of LIF and OSM in the regulation of various MMPs and TIMPs is still incompletely understood. The aims of this study were to examine the effects of LIF and OSM on MMP-1, MMP-3, and TIMP-1 production. In addition, the capacity of the LIF antagonist, MH35-BD, to block LIF and OSM induced MMP expression was examined. Primary chondrocytes, isolated from porcine metacarpophalangeal cartilage, were cultured in the presence and absence of LIF and OSM, with and without a predetermined concentration of the LIF antagonist. We analysed the levels of MMP-1, MMP-3 and TIMP-1 expression using qRT-PCR, Northern blot, and ELISA assays. The results indicate that LIF and OSM increase the expression of MMP-1, MMP-3, and TIMP-1 several fold. Furthermore their expression is reduced to basal levels in the presence of the LIF antagonist MH35-BD.


Subject(s)
Cartilage, Articular/cytology , Chondrocytes/physiology , Leukemia Inhibitory Factor , Matrix Metalloproteinase 1/metabolism , Matrix Metalloproteinase 3/metabolism , Oncostatin M/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Animals , Chondrocytes/cytology , Humans , Leukemia Inhibitory Factor/antagonists & inhibitors , Leukemia Inhibitory Factor/genetics , Leukemia Inhibitory Factor/metabolism , Matrix Metalloproteinase 1/genetics , Matrix Metalloproteinase 3/genetics , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Swine , Tissue Inhibitor of Metalloproteinase-1/genetics
3.
J Interferon Cytokine Res ; 27(4): 281-9, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17477816

ABSTRACT

Leukemia inhibitory factor (LIF) and oncostatin M (OSM) are found in appreciable concentrations in synovial fluid from patients with rheumatoid arthritis (RA) but not osteoarthritis. Accordingly, both are potential therapeutic targets in inflammatory diseases of the joints. Several LIF antagonists have been developed. They have the capacity to inhibit the biologic activities of not only LIF but also other interleukin-6 (IL-6) subfamily cytokines, including OSM. Both LIF and OSM share the same receptor, which is part of a cytokine receptor super family in which the glycoprotein 130 (gp130) subunit is a common constituent. The aim of this study was to evaluate the antagonistic potentials of two LIF mutants, LIF05 and MH35-BD. Both are mutant forms of human LIF with reduced affinity for gp130 and greater LIF receptor (LIFR) binding affinity. The results, using Ba/F3 cell proliferation assay, acute-phase protein (haptoglobin) induction analysis in HepG2 human hepatoma cells, a porcine cartilage glycosaminoglycan release assessment for proteoglycan degradation, and a collagen release assay, show that these antagonists inhibit relevant LIF, OSM, and other IL-6 subfamily cytokines in vitro albeit with differential potencies and have, therefore, therapeutic potential for treatment of RA and perhaps other diseases.


Subject(s)
Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/therapy , Receptors, OSM-LIF/antagonists & inhibitors , Animals , Cell Line , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/immunology , Glycosaminoglycans/metabolism , Humans , Hydroxyproline/metabolism , Leukemia Inhibitory Factor/genetics , Leukemia Inhibitory Factor/immunology , Oncostatin M/immunology , Receptors, OSM-LIF/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Swine
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