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Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts.
Arthritis Rheum. 2005 Jul; 52(7):2010-4.AR

Abstract

OBJECTIVE

Membrane type 1 matrix metalloproteinase (MT1-MMP) is expressed prominently in rheumatoid arthritis synovial fibroblasts (RASFs), but the specific contribution of MT1-MMP to fibroblast-mediated destruction of articular cartilage is incompletely understood. This study used gene transfer of an antisense expression construct to assess the effects of MT1-MMP inhibition on the invasiveness of RASFs.

METHODS

Retroviral gene transfer of a pLXIN vector-based antisense RNA expression construct (MT1-MMPalphaS) to MT1-MMP was used to stably transduce RASFs. Levels of MT1-MMP RNA and protein were determined by quantitative polymerase chain reaction, Western blotting, and immunocytochemistry in MT1-MMPalphaS-transduced RASFs as well as in control cells, with monitoring for 60 days. The effects of MT1-MMPalphaS on the invasiveness of RASFs were analyzed in the SCID mouse co-implantation model of RA.

RESULTS

MT1-MMPalphaS-transduced RASFs produced high levels of antisense RNA that exceeded endogenous levels of MT1-MMP messenger RNA by 15-fold and resulted in a down-regulation of MT1-MMP at the protein level. Inhibition of MT1-MMP production was maintained for 60 days and significantly reduced the invasiveness of RASFs in the SCID mouse model. Whereas prominent invasion into cartilage by non-transduced and mock-transduced RASFs was observed (mean invasion scores 3.0 and 3.1, respectively), MT1-MMPalphaS-transduced cells showed only moderate invasiveness (mean invasion score 1.8; P < 0.05).

CONCLUSION

The data demonstrate that an antisense RNA expression construct against MT1-MMP can be generated and expressed in RASFs for at least 60 days. Inhibition of MT1-MMP significantly reduces the cartilage degradation by RASFs.

Authors+Show Affiliations

Otto-von-Guericke-University, Magdeburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15986375

Citation

Rutkauskaite, Edita, et al. "Retroviral Gene Transfer of an Antisense Construct Against Membrane Type 1 Matrix Metalloproteinase Reduces the Invasiveness of Rheumatoid Arthritis Synovial Fibroblasts." Arthritis and Rheumatism, vol. 52, no. 7, 2005, pp. 2010-4.
Rutkauskaite E, Volkmer D, Shigeyama Y, et al. Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2005;52(7):2010-4.
Rutkauskaite, E., Volkmer, D., Shigeyama, Y., Schedel, J., Pap, G., Müller-Ladner, U., Meinecke, I., Alexander, D., Gay, R. E., Drynda, S., Neumann, W., Michel, B. A., Aicher, W. K., Gay, S., & Pap, T. (2005). Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 52(7), 2010-4.
Rutkauskaite E, et al. Retroviral Gene Transfer of an Antisense Construct Against Membrane Type 1 Matrix Metalloproteinase Reduces the Invasiveness of Rheumatoid Arthritis Synovial Fibroblasts. Arthritis Rheum. 2005;52(7):2010-4. PubMed PMID: 15986375.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts. AU - Rutkauskaite,Edita, AU - Volkmer,Dagmar, AU - Shigeyama,Yukio, AU - Schedel,Jörg, AU - Pap,Geza, AU - Müller-Ladner,Ulf, AU - Meinecke,Ingmar, AU - Alexander,Dorothea, AU - Gay,Renate E, AU - Drynda,Susanne, AU - Neumann,Wolfram, AU - Michel,Beat A, AU - Aicher,Wilhelm K, AU - Gay,Steffen, AU - Pap,Thomas, PY - 2005/6/30/pubmed PY - 2005/8/17/medline PY - 2005/6/30/entrez SP - 2010 EP - 4 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 52 IS - 7 N2 - OBJECTIVE: Membrane type 1 matrix metalloproteinase (MT1-MMP) is expressed prominently in rheumatoid arthritis synovial fibroblasts (RASFs), but the specific contribution of MT1-MMP to fibroblast-mediated destruction of articular cartilage is incompletely understood. This study used gene transfer of an antisense expression construct to assess the effects of MT1-MMP inhibition on the invasiveness of RASFs. METHODS: Retroviral gene transfer of a pLXIN vector-based antisense RNA expression construct (MT1-MMPalphaS) to MT1-MMP was used to stably transduce RASFs. Levels of MT1-MMP RNA and protein were determined by quantitative polymerase chain reaction, Western blotting, and immunocytochemistry in MT1-MMPalphaS-transduced RASFs as well as in control cells, with monitoring for 60 days. The effects of MT1-MMPalphaS on the invasiveness of RASFs were analyzed in the SCID mouse co-implantation model of RA. RESULTS: MT1-MMPalphaS-transduced RASFs produced high levels of antisense RNA that exceeded endogenous levels of MT1-MMP messenger RNA by 15-fold and resulted in a down-regulation of MT1-MMP at the protein level. Inhibition of MT1-MMP production was maintained for 60 days and significantly reduced the invasiveness of RASFs in the SCID mouse model. Whereas prominent invasion into cartilage by non-transduced and mock-transduced RASFs was observed (mean invasion scores 3.0 and 3.1, respectively), MT1-MMPalphaS-transduced cells showed only moderate invasiveness (mean invasion score 1.8; P < 0.05). CONCLUSION: The data demonstrate that an antisense RNA expression construct against MT1-MMP can be generated and expressed in RASFs for at least 60 days. Inhibition of MT1-MMP significantly reduces the cartilage degradation by RASFs. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/15986375/Retroviral_gene_transfer_of_an_antisense_construct_against_membrane_type_1_matrix_metalloproteinase_reduces_the_invasiveness_of_rheumatoid_arthritis_synovial_fibroblasts_ L2 - https://doi.org/10.1002/art.21156 DB - PRIME DP - Unbound Medicine ER -