IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis.
OBJECTIVE
The IKK complex regulates NF-kappaB activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKKbeta.


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.


CONCLUSIONS
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.
Schopf
Lisa
L
Millennium Pharmaceuticals, Cambridge, Massachusetts, USA. lisa.schopf@abbott.com
Savinainen
Anneli
A
Anderson
Karen
K
Kujawa
Julie
J
DuPont
Michelle
M
Silva
Matthew
M
Siebert
Elizabeth
E
Chandra
Sudeep
S
Morgan
Jennifer
J
Gangurde
Pranoti
P
Wen
Danyi
D
Lane
Joan
J
Xu
Yajun
Y
Hepperle
Michael
M
Harriman
Geraldine
G
Ocain
Timothy
T
Jaffee
Bruce
B
D000818:Animals; D001169:Arthritis, Experimental; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D002243:Carbolines / Q000494:pharmacology; D002356:Cartilage / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005620:Freund's Adjuvant; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002243:Carbolines; C514957:N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009536:Niacinamide; D005620:Freund's Adjuvant; D051550:I-kappa B Kinase