JNK1 is not essential for TNF-mediated joint disease.
Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-alpha signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis. Human TNF transgenic (hTNFtg) mice, which develop inflammatory arthritis, were intercrossed with JNK1-deficient (JNK1-/-) mice. Animals (n = 35) of all four genotypes (wild-type, JNK1-/-, hTNFtg, JNK1-/-hTNFtg) were assessed for clinical and histological signs of arthritis. Clinical features of arthritis (swelling and decreased grip strength) developed equally in hTNFtg and JNK1-/-hTNFtg mice. Histological analyses revealed no differences in the quantity of synovial inflammation and bone erosions or in the cellular composition of the synovial infiltrate. Bone destruction and osteoclast formation were observed to a similar degree in hTNFtg and JNK1-/-hTNFtg animals. Moreover, cartilage damage, as indicated by proteoglycan loss in the articular cartilage, was comparable in the two strains. Intact phosphorylation of JNK and c-Jun as well as expression of JNK2 in the synovial tissue of JNK1-/-hTNFtg mice suggests that signalling through JNK2 may compensate for the deficiency in JNK1. Thus, JNK1 activation does not seem to be essential for TNF-mediated arthritis.
Köller
Marcus
M
Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Marcus.Koeller@meduniwien.ac.at
Hayer
Silvia
S
Redlich
Kurt
K
Ricci
Romeo
R
David
Jean-Pierre
JP
Steiner
Günter
G
Smolen
Josef S
JS
Wagner
Erwin F
EF
Schett
Georg
G
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D001842:Bone and Bones / Q000473:pathology; D002358:Cartilage, Articular / Q000737:chemistry / Q000473:pathology; D003433:Crosses, Genetic; D005838:Genotype; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology; D010010:Osteoclasts / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000032:analysis; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D016037:Single-Blind Method; D013583:Synovial Membrane / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D011509:Proteoglycans; D016755:Proto-Oncogene Proteins c-jun; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8