IKKβ inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis

Objective. The IKK complex regulates NF-kappa B activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKK beta. Methods. Polyarthritis was induced in rats by injection of Freund's complete adjuvant into the hind footpad. ML120B was administered orally twice daily, either prophylactically or therapeutically. Paw volumes and body weights were measured every 2-3 days throughout the study. We assessed bone erosions by several methods: histologic evaluation, quantitative micro-computed tomography (micro-CT) imaging analysis, and measurement of type I collagen fragments in the serum. Quantitative polymerase chain reaction was used to evaluate expression of messenger RNA for genes related to inflammation and to bone and cartilage integrity. Results. Oral administration of ML120B inhibited paw swelling in a dose-dependent manner (median effective dosage 12 mg/kg twice daily) and offered significant protection against arthritis-induced weight loss as well as cartilage and bone erosion. We were able to directly demonstrate that NF-kappa B activity in arthritic joints was reduced after ML120B administration. Also, we observed that down-regulation of the NF-kappa B pathway via IKK beta inhibition dampened the chronic inflammatory process associated with rat adjuvant-induced arthritis. Conclusion. The results of the present study suggest that IKK beta inhibition is an effective therapeutic approach to treat both the inflammation and the bone/ cartilage destruction observed in RA. Methods for the determination of serum markers for bone and cartilage destruction, as well as micro-CT analysis, may aid in predicting and evaluating the therapeutic efficacy of IKK beta inhibition therapy in humans.