Blocking of interleukin-17 during reactivation of experimental arthritis prevents joint inflammation and bone erosion by decreasing RANKL and interleukin-1.
Rheumatoid arthritis is characterized by an intermittent course of disease with alternate periods of remission and relapse. T cells, and in particular the T-cell cytokine interleukin-17 (IL-17), are expected to be involved in arthritic flares. Here, we report that neutralizing endogenous IL-17 during reactivation of antigen-induced arthritis prevents joint inflammation and bone erosion. Synovial IL-17 mRNA expression was clearly up-regulated during primary arthritis and was further enhanced after antigen rechallenge. Neutralization of IL-17 significantly prevented joint swelling at day 1 of flare and significantly suppressed joint inflammation and cartilage proteoglycan depletion at day 4, as assessed by histology. Blocking IL-17 also clearly reduced bone erosions. Cathepsin K, a marker of osteoclast-like activity, and synovial RANKL mRNA expression were both suppressed. The degree of bone erosions strongly correlated with the severity of joint inflammation, suggesting that anti-IL-17 treatment reduced bone erosion by suppressing joint inflammation. Interestingly, blocking IL-17 suppressed synovial expression of both IL-1beta and tumor necrosis factor-alpha, whereas blocking IL-1 did not affect tumor necrosis factor-alpha levels. These data indicate that IL-17 is an important upstream mediator in joint pathology during flare-up of experimental arthritis.
Department of Rheumatology, Experimental Rheumatology and Advanced Therapeutics, Radboud University Nijmegen Medical Center, 189, Geert Grooteplein Zuid 26-28, PO Box 9101, 6500 HB Nijmegen, The Netherlands. m.koenders@reuma.umcn.nl
Marije I
MI
Koenders
Erik
E
Lubberts
Birgitte
B
Oppers-Walgreen
Liduine
L
van den Bersselaar
Monique M
MM
Helsen
Franco E
FE
Di Padova
Annemieke M H
AM
Boots
Hermann
H
Gram
Leo A B
LA
Joosten
Wim B
WB
van den Berg
D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology; D001842:Bone and Bones / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D007596:Joints / Q000276:immunology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D002352:Carrier Proteins; D007375:Interleukin-1; D020381:Interleukin-17; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D002403:Cathepsins; D056657:Cathepsin K; C534132:Ctsk protein, mouse