Abstract
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-α 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.
Highlights
Proinflammatory cytokines bind to their receptors on the plasma membrane and transmit the stimulatory effects to the nucleus via intracellular signalling molecules
Tumour necrosis factor (TNF)-induced clinical signs of arthritis develop independently of JNK1 To study the role in vivo of JNK1 activation in TNF-mediated arthritis, we intercrossed human TNF transgenic (hTNFtg) with JNK1-/- mice
There was no significant difference between the hTNFtg and JNK1-/-hTNFtg mice at any time of the analysis (Fig. 1a)
Summary
Proinflammatory cytokines bind to their receptors on the plasma membrane and transmit the stimulatory effects to the nucleus via intracellular signalling molecules. These cytokines are considered as promising therapeutic targets. Cellular activation by TNF-α is a critical step in chronic synovial inflammation and progressive joint destruction This is supported by the overwhelming effects of TNF blockade, which has revolutionized the therapy of rheumatoid arthritis (RA). The hypothesis is supported by animal models in which specific overexpression of TNF-α is sufficient to cause chronic destructive arthritis [6] Increased levels of this cytokine in the synovial fluid and tissue of RA patients have been reported [7,8,9]).)
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