Abstract | OBJECTIVE: 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-kappaB activity in arthritic joints was reduced after ML120B administration. Also, we observed that down-regulation of the NF-kappaB pathway via IKKbeta inhibition dampened the chronic inflammatory process associated with rat adjuvant-induced arthritis. CONCLUSION: The results of the present study suggest that IKKbeta 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 IKKbeta inhibition therapy in humans.
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Authors | Lisa Schopf, Anneli Savinainen, Karen Anderson, Julie Kujawa, Michelle DuPont, Matthew Silva, Elizabeth Siebert, Sudeep Chandra, Jennifer Morgan, Pranoti Gangurde, Danyi Wen, Joan Lane, Yajun Xu, Michael Hepperle, Geraldine Harriman, Timothy Ocain, Bruce Jaffee |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 54
Issue 10
Pg. 3163-73
(Oct 2006)
ISSN: 0004-3591 [Print] United States |
PMID | 17009244
(Publication Type: Journal Article)
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Chemical References |
- Carbolines
- N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide
- NF-kappa B
- Tumor Necrosis Factor-alpha
- Niacinamide
- Freund's Adjuvant
- I-kappa B Kinase
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Topics |
- Animals
- Arthritis, Experimental
- Arthritis, Rheumatoid
(chemically induced, metabolism, physiopathology)
- Bone and Bones
(metabolism, pathology)
- Carbolines
(pharmacology)
- Cartilage
(metabolism, pathology)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Female
- Freund's Adjuvant
- Gene Expression Regulation
- I-kappa B Kinase
(antagonists & inhibitors, genetics, metabolism)
- NF-kappa B
(genetics, metabolism)
- Niacinamide
(analogs & derivatives, pharmacology)
- Rats
- Rats, Inbred Lew
- Tumor Necrosis Factor-alpha
(metabolism)
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