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JNK1 is not essential for TNF-mediated joint disease.

Köller M, Hayer S, Redlich K, Ricci R, David JP, Steiner G, Smolen JS, Wagner EF, Schett G - Arthritis Res. Ther. (2004)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Marcus.Koeller@meduniwien.ac.at

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-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.

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Clinical course of arthritis in human tumour necrosis factor transgenic (hTNFtg) and JNK1-/-hTNFtg mice. Joint swelling (a) and grip strength (b) were assessed. No statistically significant differences between the two groups were detected. Vertical bars indicate standard deviation. Control animals (wild-type and JNK1-/-) showed no signs of arthritis (not shown). JNK, c-Jun N-terminal kinase.
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Figure 1: Clinical course of arthritis in human tumour necrosis factor transgenic (hTNFtg) and JNK1-/-hTNFtg mice. Joint swelling (a) and grip strength (b) were assessed. No statistically significant differences between the two groups were detected. Vertical bars indicate standard deviation. Control animals (wild-type and JNK1-/-) showed no signs of arthritis (not shown). JNK, c-Jun N-terminal kinase.

Mentions: To study the role in vivo of JNK1 activation in TNF-mediated arthritis, we intercrossed hTNFtg with JNK1-/- mice. The offspring of all four genotypes (wt, hTNFtg, JNK1-/-, and JNK1-/-hTNFtg) were born at Mendelian frequency and were viable. To evaluate arthritis, we assessed joint swelling and grip strength weekly in all four genotypes. Neither wt nor JNK1-/- mice developed any signs of paw swelling, and both maintained normal grip strength (data not shown). In contrast, the hTNFtg animals developed joint swelling at 6 weeks of age, which increased to a maximum at week 10 (P < 0.05 in comparison with wt and JNK1-/-). In the JNK1-/-hTNFtg group, joint swelling started at age 7 weeks and increased significantly thereafter (P < 0.05 in comparison with wt and JNK1-/-). There was no significant difference between the hTNFtg and JNK1-/-hTNFtg mice at any time of the analysis (Fig. 1a). In addition, grip strength significantly decreased in both hTNFtg and JNK1-/-hTNFtg strains, but no significant difference between the two genotypes was found (Fig. 1b). Thus, overexpression of TNF-α induces clinical signs of arthritis also in the absence of JNK1.


JNK1 is not essential for TNF-mediated joint disease.

Köller M, Hayer S, Redlich K, Ricci R, David JP, Steiner G, Smolen JS, Wagner EF, Schett G - Arthritis Res. Ther. (2004)

Clinical course of arthritis in human tumour necrosis factor transgenic (hTNFtg) and JNK1-/-hTNFtg mice. Joint swelling (a) and grip strength (b) were assessed. No statistically significant differences between the two groups were detected. Vertical bars indicate standard deviation. Control animals (wild-type and JNK1-/-) showed no signs of arthritis (not shown). JNK, c-Jun N-terminal kinase.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064897&req=5

Figure 1: Clinical course of arthritis in human tumour necrosis factor transgenic (hTNFtg) and JNK1-/-hTNFtg mice. Joint swelling (a) and grip strength (b) were assessed. No statistically significant differences between the two groups were detected. Vertical bars indicate standard deviation. Control animals (wild-type and JNK1-/-) showed no signs of arthritis (not shown). JNK, c-Jun N-terminal kinase.
Mentions: To study the role in vivo of JNK1 activation in TNF-mediated arthritis, we intercrossed hTNFtg with JNK1-/- mice. The offspring of all four genotypes (wt, hTNFtg, JNK1-/-, and JNK1-/-hTNFtg) were born at Mendelian frequency and were viable. To evaluate arthritis, we assessed joint swelling and grip strength weekly in all four genotypes. Neither wt nor JNK1-/- mice developed any signs of paw swelling, and both maintained normal grip strength (data not shown). In contrast, the hTNFtg animals developed joint swelling at 6 weeks of age, which increased to a maximum at week 10 (P < 0.05 in comparison with wt and JNK1-/-). In the JNK1-/-hTNFtg group, joint swelling started at age 7 weeks and increased significantly thereafter (P < 0.05 in comparison with wt and JNK1-/-). There was no significant difference between the hTNFtg and JNK1-/-hTNFtg mice at any time of the analysis (Fig. 1a). In addition, grip strength significantly decreased in both hTNFtg and JNK1-/-hTNFtg strains, but no significant difference between the two genotypes was found (Fig. 1b). Thus, overexpression of TNF-α induces clinical signs of arthritis also in the absence of JNK1.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Marcus.Koeller@meduniwien.ac.at

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-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.

Show MeSH
Related in: MedlinePlus