The SCID mouse model: novel therapeutic targets - lessons from gene transfer
- PMID: 12904892
- DOI: 10.1007/s00281-003-0126-2
The SCID mouse model: novel therapeutic targets - lessons from gene transfer
Abstract
The hallmark of rheumatoid arthritis (RA) is progressive destruction of the joints, preceded and accompanied by synovial hyperplasia and chronic inflammation. Spontaneous and induced animal models of RA reflect predominantly the inflammatory aspects of the disease. To reproduce the destruction of cartilage and bone mediated by an activated synovium, it was desirable to develop models that allow the dissection of cellular and molecular components derived from human tissue. The SCID mouse co-implantation model of human RA focuses on RA synovial fibroblasts (RA-SF) and their role in cartilage destruction. The model has provided the best evidence that RA-SF contribute significantly to matrix degradation, even in the absence of human lymphocytes and macrophages, since highly purified RA-SF invade the co-implanted normal human cartilage. Moreover, it became clear that they maintained their aggressive phenotype over long periods of time, particularly at sites of invasion into the co-implanted human cartilage. Targeting different signaling molecules, cytokines and matrix-degrading enzymes by soluble receptors, antagonists or negative mutants in the SCID mouse model of RA has implicated many of them in the mechanisms leading to cartilage destruction. However, since inhibition of a single molecule or pathway is not sufficient to inhibit the aggressive behavior of RA-SF it appears necessary to co-express in the synoviocytes genes for two or even more antagonists of e.g. cytokines, matrix-degrading enzymes or molecules interfering specifically with signaling pathways involved in the apoptosis of RA-SF. Based on the recent observation that the L1 (line-1) endogenous retroviral element appears responsible for the cytokine- independent activation via the MAPK p38delta, the current understanding of disease pathogenesis suggests that both the cytokine-dependent as well as the cytokine-independent pathways of joint destruction must be inhibited. Modulation of both pathways by gene transfer approaches in the SCID mouse model is a feasible method aimed at identifying novel targets for the prevention of cartilage destruction in RA.
Similar articles
-
[Gene therapy in rheumatoid arthritis: new aspects].Dtsch Med Wochenschr. 2008 Aug;133(34-35):1737-41. doi: 10.1055/s-0028-1082797. Dtsch Med Wochenschr. 2008. PMID: 18696407 Review. German.
-
E2F decoy oligodeoxynucleotide ameliorates cartilage invasion by infiltrating synovium derived from rheumatoid arthritis.Int J Mol Med. 2006 Aug;18(2):257-65. Int J Mol Med. 2006. PMID: 16820932
-
Cartilage degradation and invasion by rheumatoid synovial fibroblasts is inhibited by gene transfer of TIMP-1 and TIMP-3.Gene Ther. 2003 Feb;10(3):234-42. doi: 10.1038/sj.gt.3301871. Gene Ther. 2003. PMID: 12571631
-
[Rheumatoid arthritis: new developments in the pathogenesis with special reference to synovial fibroblasts].Z Rheumatol. 2001 Oct;60(5):309-18. doi: 10.1007/s003930170030. Z Rheumatol. 2001. PMID: 11759230 Review. German.
-
Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model.Arthritis Rheum. 1999 Mar;42(3):490-7. doi: 10.1002/1529-0131(199904)42:3<490::AID-ANR14>3.0.CO;2-L. Arthritis Rheum. 1999. PMID: 10088772
Cited by
-
Rheumatoid synovial fibroblasts differentiate into distinct subsets in the presence of cytokines and cartilage.Arthritis Res Ther. 2016 Nov 18;18(1):270. doi: 10.1186/s13075-016-1156-1. Arthritis Res Ther. 2016. PMID: 27863512 Free PMC article.
-
Mechanisms of tissue damage in arthritis.Semin Immunopathol. 2014 Sep;36(5):531-40. doi: 10.1007/s00281-014-0442-8. Epub 2014 Sep 12. Semin Immunopathol. 2014. PMID: 25212687 Review.
-
TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis.Clin Exp Immunol. 2010 Jul 1;161(1):71-80. doi: 10.1111/j.1365-2249.2010.04163.x. Epub 2010 May 10. Clin Exp Immunol. 2010. PMID: 20491788 Free PMC article.
-
Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis.Immunol Rev. 2010 Jan;233(1):233-55. doi: 10.1111/j.0105-2896.2009.00859.x. Immunol Rev. 2010. PMID: 20193003 Free PMC article. Review.
-
Effect of the oral application of a highly selective MMP-13 inhibitor in three different animal models of rheumatoid arthritis.Ann Rheum Dis. 2010 May;69(5):898-902. doi: 10.1136/ard.2008.106021. Epub 2009 Jun 3. Ann Rheum Dis. 2010. PMID: 19497915 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical