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Selective Inhibition of Membrane Type 1 Matrix Metalloproteinase Abrogates Progression of Experimental Inflammatory Arthritis: Synergy With Tumor Necrosis Factor Blockade
Author(s) -
Kaneko Kazuyo,
Williams Richard O.,
Dransfield Daniel T.,
Nixon Andrew E.,
Sandison Ann,
Itoh Yoshifumi
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39414
Subject(s) - tumor necrosis factor alpha , cytokine , medicine , arthritis , matrix metalloproteinase , cancer research , rheumatoid arthritis , type ii collagen , immunology , lipopolysaccharide , cartilage , inflammation , anatomy
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. Conclusion 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.