Use of molecular imaging to quantify response to IKK-2 inhibitor treatment in murine arthritis.
OBJECTIVE
The NF-kappaB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF-kappaB activity is regulated by the IKK-2 kinase during inflammatory responses. To elucidate how IKK-2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody-induced arthritis.


METHODS
ML120B, a potent, small molecule inhibitor of IKK-2, was administered to arthritic animals, and disease activity was monitored. NF-kappaB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase-polymerase chain reaction was used to evaluate gene expression in joints. Protease-activated near-infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.


RESULTS
Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF-kappaB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF-kappaB pathway, i.e., KC, epithelial neutrophil-activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor alpha, interleukin-1beta, interleukin-6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.


CONCLUSIONS
Our data demonstrate that IKK-2 inhibition in the murine model of antibody-induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.
Izmailova
Elena S
ES
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. Elena.Izmailova@mpi.com
Paz
Nancy
N
Alencar
Herlen
H
Chun
Miyoung
M
Schopf
Lisa
L
Hepperle
Michael
M
Lane
Joan H
JH
Harriman
Geraldine
G
Xu
Yajun
Y
Ocain
Timothy
T
Weissleder
Ralph
R
Mahmood
Umar
U
Healy
Aileen M
AM
Jaffee
Bruce
B
D000284:Administration, Oral; D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002243:Carbolines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013050:Spectrometry, Fluorescence / Q000379:methods; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D015854:Up-Regulation / Q000187:drug effects
D018501:Antirheumatic Agents; D002243:Carbolines; D004791:Enzyme Inhibitors; C514957:N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide; D016328:NF-kappa B; D012333:RNA, Messenger; D009536:Niacinamide; D051550:I-kappa B Kinase