Rheumatoid arthritis (RA) is a disabling autoimmune disease of the synovial joints, characterized by chronic inflammation and the destruction of cartilage and bone. Proinflammatory cytokines, such as tumour-necrosis factor-α (TNF-α) and interleukin 6 (IL-6), have been implicated in the pathogenesis of this disease. Recent work by Shouda and colleagues in The Journal of Clinical Investigation shows that blocking cytokine signalling by inducing the expression of the cytokine signal regulator SOC3/CIS3 (suppressor of cytokine signalling 3/cytokine-inducible SH2 protein 3) effectively reduces bone destruction in mouse autoimmune arthritis, thus representing a possible new therapeutic target.

Earlier work, both in vitro and in vivo, established a role for IL-6 in the development of arthritis. IL-6 acts by activating Janus kinase (JAK) tyrosine kinases and the transcription factor STAT3 (signal transducer and activator of transcription 3). SOCS3 was previously cloned by Shouda's group, and was shown to inhibit JAK kinases and to negatively regulate STAT3 functions. As SOCS3 is strongly induced by IL-6, the authors decided to investigate whether SOCS3 plays a negative regulatory role in the progression of RA.

To investigate the importance of STAT3 activation and SOCS3 induction in RA, adenoviral transfer was used to overexpress SOCS3 or a dominant negative form of STAT3 (dnSTAT3) in synoviocytes isolated from patients with RA. The proliferation of cells infected with either of these constructs was significantly reduced, as was the production of IL-6 and TNF-α. These results show that the proliferation and cytokine production of RA-synoviocytes in vitro is dependent on JAK/STAT3 signalling and that these processes can be inhibited by the expression of SOCS3 or dnSTAT3.

Do these constructs have any effect on the development of arthritis in vivo? Shouda and co-workers injected SOCS3 and dnSTAT3 adenovirus into the ankle joints of mice prone to antigen-induced arthritis (AIA) or collagen-induced arthritis (CIA). In the AIA model, both dnSTAT3 and CIS3 drastically reduced the severity of arthritis and joint swelling compared with control animals. However, in the CIA model the dnSTAT3 adenovirus was less effective than SOCS3, which significantly reduced the severity of arthritis. Finally, the SOCS3 adenovirus was also shown to be an effective treatment for established arthritis.

The authors conclude that adenovirus-mediated gene transfer of the SOCS3 gene could represent a new approach for effectively blocking the pathogenesis of RA.