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Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3

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Author: Laan, W.H. van der · Quax, P.H.A. · Seemayer, C.A. · Huisman, L.G.M. · Pieterman, E.J. · Grimbergen, J.M. · Verheijen, J.H. · Breedveld, F.C. · Gay, R.E. · Gay, S. · Huizinga, T.W.J. · Pap, T.
Type:article
Date:2003
Institution: Gaubius Instituut TNO
Source:Gene Therapy, 3, 10, 234-242
Identifier: 236959
doi: doi:10.1038/sj.gt.3301871
Keywords: Adenoviridae · Animals · Arthritis, Rheumatoid · Cartilage, Articular · Cell Division · Fibroblasts · Gene Expression · Gene Therapy · Genetic Vectors · Humans · Matrix Metalloproteinases · Mice · Mice, SCID · Synovial Membrane · Tissue Inhibitor of Metalloproteinase-1 · Tissue Inhibitor of Metalloproteinase-3 · Transduction, Genetic · Adenoviridae · Animalia

Abstract

Matrix metalloproteinases (MMPs) are believed to be pivotal enzymes in the invasion of articular cartilage by synovial tissue in rheumatoid arthritis (RA). Here, we investigated the effects of gene transfer of tissue inhibitors of metalloproteinases (TIMPs) on the invasiveness of RA synovial fibroblasts (RASF) in vitro and in vivo. Adenoviral vectors (Ad) were used for gene transfer. The effects of AdTIMP-1 and AdTIMP-3 gene transfer on matrix invasion were investigated in vitro in a transwell system. Cartilage invasion in vivo was studied in the SCID mouse coimplantation model for 60 days. In addition, the effects of AdTIMP-1 and AdTIMP-3 on cell proliferation were investigated. A significant reduction in invasiveness was demonstrated in vitro as well as in vivo in both the AdTIMP-1- and AdTIMP-3-transduced RASF compared with untransduced SF or SF that were transduced with control vectors. In vitro, the number of invading cells was reduced to 25% (P < 0.001) in the AdTIMP-1-transduced cells and to 13% (P < 0.0001) in the AdTIMP-3-transduced cells (% of untransduced cells). Cell proliferation was significantly inhibited by AdTIMP-3 and, less, by AdTIMP-1. In conclusion, overexpression of TIMP-1 and TIMP-3 by Ad gene transfer results in a marked reduction of the invasiveness of RASF in vitro and in the SCID mouse model. Apart from the inhibition of MMPs, a reduction in proliferation rate may contribute to this effect. These results suggest that overexpression of TIMPs, particularly TIMP-3 at the invasive front of pannus tissue, may provide a novel therapeutic strategy for inhibiting joint destruction in RA. Chemicals/CAS: marimastat, 154039-60-8; tissue inhibitor of metalloproteinase 1, 140208-24-8; tissue inhibitor of metalloproteinase 3, 145809-21-8, 164781-40-2; Matrix Metalloproteinases, EC 3.4.24.-; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-3