Direct inhibition of NF-kappa B blocks bone erosion associated with inflammatory arthritis.
Inflammatory arthritis is associated with devastating joint tissue destruction and periarticular bone erosion. Although secreted products of infiltrating immune cells perpetuate the inflammatory response, the osteolytic component of this disease is a direct result of localized recruitment and activation of osteoclasts. Given that NF-kappaB plays a central role in both processes, the function of this transcription factor was examined. Using a mouse model of autoreactive Ig transfer that engenders inflammatory arthritis, we show numerous osteoclasts in the articular joint tissue associated with progressive periarticular osteolytic lesions. Moreover, cells retrieved from these joints exhibit heightened NF-kappaB activity. Importantly, direct administration of dominant negative*I-kappaB or tyrosine 42-mutated I-kappaB (Y42F*I-kappaB) proteins into mice before induction of the disease attenuates in vivo activation of the transcription factor. More importantly, these I-kappaB mutant forms significantly inhibit in vivo production of TNF and receptor activator of NF-kappaB ligand, and block joint swelling, osteoclast recruitment, and osteolysis. Thus, NF-kappaB appears to be the centerpiece of inflammatory-osteolytic arthritis and direct inhibition of this transcription factor by unique and novel I-kappaB mutant proteins blocks manifestation of the disease.
Clohisy
John C
JC
Department of Orthopaedic Research Laboratory, Barnes-Jewish Hospital at Washington University School of Medicine, St. Louis, MO 63110, USA.
Roy
Bhabesh C
BC
Biondo
Christine
C
Frazier
Elfaridah
E
Willis
David
D
Teitelbaum
Steven L
SL
Abu-Amer
Yousef
Y
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D002352:Carrier Proteins / Q000097:blood / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D006614:Hindlimb; D020672:I-kappa B Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D007116:Immunization, Passive; D007136:Immunoglobulins / Q000008:administration & dosage / Q000097:blood; D018836:Inflammation Mediators / Q000008:administration & dosage* / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008562:Membrane Glycoproteins / Q000097:blood / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics / Q000502:physiology*; D010010:Osteoclasts / Q000473:pathology; D010014:Osteolysis / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002352:Carrier Proteins; D020672:I-kappa B Proteins; D007136:Immunoglobulins; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha