Skip to main content


Activation of Synovial Fibroblasts in Rheumatoid Arthritis

Full text

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.


  1. 1.

    Müller-Ladner U, Gay RE, Gay S: Signalling and effector pathways. Curr Opin Rheumatol. 1999, 11: 194-201. 10.1097/00002281-199905000-00008.

  2. 2.

    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.

  3. 3.

    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.

  4. 4.

    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.

  5. 5.

    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.

  6. 6.

    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.

Download references

Author information

Rights and permissions

Reprints and Permissions

About this article


  • Rheumatoid Arthritis
  • Full Text
  • SCID Mouse
  • Synovial Fibroblast
  • Joint Destruction