Activation of Synovial Fibroblasts in Rheumatoid Arthritis
© Current Science Ltd 2000
Published: 15 November 1999
Activation of synovial fibroblasts (SF) by upregulation of proto-oncogenes is thought to play a major role in rheumatoid joint destruction. To explore distinct signaling pathways in this activation we used retroviral gene transfer in the SCID mouse model. Specifically, we transferred dominant negative (dn) mutants, such as dn Raf-1 and dn c-myc to inhibit the Ras-Raf-MAPK cascade as well as the cascade involving myc. FLAG-tagged constructs used in this study were cloned into the retroviral vector LXSN. The data show that both Raf- as well as myc-dependent pathways contribute to the activation of synovial fibroblasts in RA.
Since mutations in PTEN have been described in cancer and associated with their invasiveness we studied the expression of this novel tumor-suppressor in RA. Although, no mutations of PTEN could be detected in RA synovium, only 40% of cultured RA-SF expressed PTEN, and a down-regulation was observed at sites of invasion into cartilage. These findings suggest that endogenous or autocrine down-regulation of this tumor-suppressor may contribute to the invasive behavior of RA-SF by maintaining their aggressive phenotype at sites of cartilage destruction in RA. Most interestingly, the same SF found at these sites are also the major producers of interleukin-16, a strong chemoattractant for CD4+ cells.
- Müller-Ladner U, Gay RE, Gay S: Signalling and effector pathways. Curr Opin Rheumatol. 1999, 11: 194-201. 10.1097/00002281-199905000-00008.PubMedView ArticleGoogle Scholar
- Müller-Ladner U, Gay S: The SCID mouse: a novel experimental model for gene therapy in human rheumatoid arthritis. Drugs Today. 1999, 35: 379-388.PubMedView ArticleGoogle Scholar
- Neidhart M, Wehrli R, Brühlmann P, Michel BA, Gay RE, Gay S: Synovial fluid CD146 (MUC 18), a marker for synovial membrane angiogenesis in rheumatoid arthritis. Arthritis Rheum. 1999, 42: 622-630. 10.1002/1529-0131(199904)42:4<622::AID-ANR4>3.0.CO;2-Y.PubMedView ArticleGoogle Scholar
- Franz J, Kolb SA, Hummel KM, et al: Interleukin-16, produced by synovial fibroblasts, mediates chemoattractant for CD4+ T lymphocytes in rheumatoid arthritis. Eur J Immunol . 1998, 28: 2661-2671. 10.1002/(SICI)1521-4141(199809)28:09<2661::AID-IMMU2661>3.0.CO;2-N.PubMedView ArticleGoogle Scholar
- Jorgensen C, Gay S: Gene therapy in osteoarticular diseases: where are we?. Immunol Today. 1998, 19: 387-391. 10.1016/S0167-5699(98)01296-1.PubMedView ArticleGoogle Scholar
- Müller-Ladner U, Evans CH, Franklin BN, et al: Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID Mouse model. Arthritis Rheum. 1999, 41: 490-497. 10.1002/1529-0131(199904)42:3<490::AID-ANR14>3.0.CO;2-L.View ArticleGoogle Scholar