NF-KB Inhibitor Effective in Mouse Model of Rheumatoid Arthritis

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NF-KB Inhibitor Effective in Mouse Model of Rheumatoid Arthritis

J Rheumatol 2005;32:1440-1447.

http://www.medscape.com/viewarticle/511272?src=mp

A compound that inhibits the transcription factor nuclear factor-kappa-B

(NF-kB) signaling pathway is effective against collagen-induced arthritis in

mice, a model of human rheumatoid arthritis, Japanese investigators report.

" Therapeutic strategies for inhibiting the NF-kB pathway are considered

promising because activation of NF-kB helps mediate prolonged inflammation

of RA, " investigators note in the August issue of The Journal of

Rheumatology.

In particular, the I-kappa-B kinase (IKK) complex, which stimulates genes

involved in inflammation, is thought to be an important molecular target

because the majority of inflammatory signaling pathways mediated by NF-kB

involve IKK activation.

Dr. Yuko Okazaki and colleagues from the University of Tokyo studied the

effects of the IKK inhibitor IMD-0560 on rheumatoid fibroblast-like

synoviocytes and murine collagen-induced arthritis.

In cultured fibroblast-like synoviocytes, IMD-0560 curbed the

phosphorylation of IkB-alpha by reducing IKK-beta activity, thereby

preventing subsequent NF-kB activation.

Moreover, IMD-0560 suppressed the production of several proinflammatory

cytokines including interleukin 6 (IL-6), IL-8, and monocyte chemoattractant

protein-1 (MCP-1) in these cells. The compound also inhibited

fibroblast-like synoviocyte proliferation and cell-cycle progression.

In the mouse collagen-induced arthritis model, intraperitoneal injection of

IMD-0560 at the time of arthritis induction led to a significant,

dose-dependent reduction in the incidence and severity of arthritis.

" Importantly, cartilage and bone erosion was almost completely prevented by

administration of IMD-0560, " Dr. Okazaki and colleagues note.

" We therefore have clearly demonstrated a prophylactic effect of IMD-0560 on

mouse collagen type II-induced arthritis, " the team notes. They are now

looking at the effects of IMD-0560 administration after the onset of

collagen type II-induced arthritis, but have yet to see a significant

therapeutic effect.

" IMD-0560 did not appear to have significant toxicity for rheumatoid

fibroblast-like synoviocytes in vitro, but further examination of the in

vivo safety of this compound is necessary, " they write.

These findings suggest to the team that IMD-0560 " is a promising new

therapeutic agent for RA. "