title: Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3.
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 co-implantation 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.
authors.affiliation: Division of Vascular and Connective Tissue Research, Gaubius Laboratory, TNO Prevention and Health, Leiden, Switzerland.
authors.forename: W H
authors.initials: WH
authors.lastname: van der Laan
authors.forename: P H A
authors.initials: PH
authors.lastname: Quax
authors.forename: C A
authors.initials: CA
authors.lastname: Seemayer
authors.forename: L G M
authors.initials: LG
authors.lastname: Huisman
authors.forename: E J
authors.initials: EJ
authors.lastname: Pieterman
authors.forename: J M
authors.initials: JM
authors.lastname: Grimbergen
authors.forename: J H
authors.initials: JH
authors.lastname: Verheijen
authors.forename: F C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: R E
authors.initials: RE
authors.lastname: Gay
authors.forename: S
authors.initials: S
authors.lastname: Gay
authors.forename: T W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: T
authors.initials: T
authors.lastname: Pap
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000473:pathology / Q000628:therapy*; D002358:Cartilage, Articular / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division; D005347:Fibroblasts / Q000473:pathology; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D013583:Synovial Membrane / Q000201:enzymology / Q000473:pathology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases