Title
Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3
Author
van der Laan, W.H.
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.
Gaubius Instituut TNO
Publication year
2003
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
Subject
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
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DOI
https://doi.org/10.1038/sj.gt.3301871
TNO identifier
236959
ISSN
0969-7128
Source
Gene Therapy, 10 (3), 234-242
Document type
article