title: Selective Inhibition of Membrane Type 1 Matrix Metalloproteinase Abrogates Progression of Experimental Inflammatory Arthritis: Synergy With Tumor Necrosis Factor Blockade.
abstract: OBJECTIVE
  In rheumatoid arthritis (RA), destruction of articular cartilage by the inflamed synovium is considered to be driven by increased activities of proteolytic enzymes, including matrix metalloproteinases (MMPs). The purpose of this study was to investigate the therapeutic potential of selective inhibition of membrane type 1 MMP (MT1-MMP) and its combination with tumor necrosis factor (TNF) blockage in mice with collagen-induced arthritis (CIA).
  
  
  METHODS
  CIA was induced in DBA/1 mice by immunization with bovine type II collagen. From the onset of clinical arthritis, mice were treated with MT1-MMP selective inhibitory antibody DX-2400 and/or TNFR-Fc fusion protein. Disease progression was monitored daily, and serum, lymph nodes, and affected paws were collected at the end of the study for cytokine and histologic analyses. For in vitro analysis, bone marrow-derived macrophages were stimulated with lipopolysaccharide for 24 hours in the presence of DX-2400 and/or TNFR-Fc to analyze cytokine production and phenotype.
  
  
  RESULTS
  DX-2400 treatment significantly reduced cartilage degradation and disease progression in mice with CIA. Importantly, when combined with TNF blockade, DX-2400 acted synergistically, inducing long-term benefit. DX-2400 also inhibited the up-regulation of interleukin-12 (IL-12)/IL-23 p40 via polarization toward an M2 phenotype in bone marrow-derived macrophages. Increased production of IL-17 induced by anti-TNF, which correlated with an incomplete response to anti-TNF, was abrogated by combined treatment with DX-2400 in CIA.
  
  
  CONCLUSIONS
  Targeting MT1-MMP provides a potential strategy for joint protection, and its combination with TNF blockade may be particularly beneficial in RA patients with an inadequate response to anti-TNF therapy.
authors: Kennedy Institute of Rheumatology and University of Oxford, Oxford, UK.
authors: Kazuyo
authors: K
authors: Kaneko
authors: Kennedy Institute of Rheumatology and University of Oxford, Oxford, UK.
authors: Richard O
authors: RO
authors: Williams
authors: Dyax Corporation, Burlington, Massachusetts.
authors: Daniel T
authors: DT
authors: Dransfield
authors: Dyax Corporation, Burlington, Massachusetts.
authors: Andrew E
authors: AE
authors: Nixon
authors: Charing Cross Hospital and Imperial College London, London, UK.
authors: Ann
authors: A
authors: Sandison
authors: Kennedy Institute of Rheumatology and University of Oxford, Oxford, UK.
authors: Yoshifumi
authors: Y
authors: Itoh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D002358:Cartilage, Articular / Q000187:drug effects* / Q000473:pathology; D018450:Disease Progression; D000068800:Etanercept / Q000494:pharmacology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000187:drug effects / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000187:drug effects* / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D053511:Matrix Metalloproteinase 14 / Q000187:drug effects* / Q000276:immunology; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000608273:DX-2400; C556062:IL10 protein, mouse; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D008070:Lipopolysaccharides; D061965:Matrix Metalloproteinase Inhibitors; C507096:Mmp14 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D053511:Matrix Metalloproteinase 14; D000068800:Etanercept