hTNFtg Animals Research Articles

OP0298 The Role of CD11c+ Dendritic Cells in Inflammatory Arthritis

BackgroundDendritic cells (DCs) play an important role in bridging the innate and the adaptive immune response by serving as antigen presenting cells and are therefore implicated in the initiation of...

SAT0057 Functional impairment in an animal model for rheumatoid arthritis assessed as changes in gait is due to joint destruction but not synovial inflammation per SE

ObjectivesTo investigate the individual impact of synovial inflammation, subchondral bone erosion or cartilage damage on functional impairment in an animal model of Rheumatoid Arthritis (RA).MethodsWe analysed gait profiles in human...

AB0174 Muscle wasting in HTNFTG mice; an animal model for rheumatoid arthritis; due to increased cathepsin l expression

ObjectivesTo investigate the impact of systemic inflammation on skeletal muscles in human tumor necrosis factor transgenic (hTNFtg) animals.MethodsWe isolated triceps surae, as well as rectus abdominis muscles from hTNFtg animals...

THU0026 P62/SQSTM1 links reactive oxygen species formation and obesity to increased tnfalpha-mediated joint destruction via its signalling domains

BackgroundThe multidomain protein p62/SQSTM1 modulates important signalling pathways responsible for osteoclastogenesis, cell proliferation and polarity. Furthermore, it also regulates protein degradation by autophagy, the ubiquitin proteasome system or sequestration. Although...

Combined depletion of interleukin-1 and interleukin-6 does not exceed single depletion of interleukin -1 in TNF-mediated arthritis

Background Previous studies demonstrated a regulatory role of interleukin 1 (IL-1) in inflammatory cartilage damage and bone destruction in human tumour necrosis factor transgenic (hTNFtg) mice, an animal model for rheumatoid arthritis. Moreover, blocking of IL-6 has been shown to reduce local bone erosions in this model. Therefore the authors wanted to investigate the effect of a combined depletion of IL-1 and IL-6 on the development and severity of inflammatory, erosive arthritis. Methods The authors first crossed IL-1α and s deficient (IL-1 −/− ) mice with IL-6 −/− mice to generate IL-1 −/− IL-6 −/− double knockout mice. The authors next intercrossed these animals with arthritogenic hTNFtg mice to receive IL-1 −/− IL-6 −/− hTNFtg mice. The authors weekly assessed clinical signs of arthritis in hTNFtg, IL-1 −/− hTNFtg mice, IL-6 −/− hTNFtg mice and IL-1 −/− IL-6 −/− hTNFtg mice starting from week 4 after birth until week 16. The authors stained decalcified paw sections from all four genotypes with H&E to determine the amount of inflammatory synovial pannus formation, with tartrate-resistant acid phosphatase (TRAP) to evaluate the number of synovial osteoclasts and the occurrence of subchondral bone erosions, with toluidine-blue to assess articular cartilage damage. Quantitative analysis of histopathological changes were performed using the Osteomeasure Software System. Results The authors found a significant reduction in the clinical signs of arthritis, indicated by an increase of paw swelling and a decrease in grip strength, in IL-1 −/− IL-6 −/− hTNFtg mice when compared to their hTNFtg littermates. In line with these findings the authors observed a significant decrease in synovial inflammation in IL-1 −/− IL-6 −/− hTNFtg mice when compared to hTNFtg animals. Moreover, the number of synovial TRAP+ osteoclasts was markedly diminished in IL-1 −/− IL-6 −/− hTNFtg mice and reduced osteoclast formation was accompanied by significantly less subchondral bone erosions. Additionally, the authors found a conserved articular cartilage structure showing almost no cartilage degradation in IL-1 −/− IL-6 −/− hTNFtg mice compared to their hTNFtg littermates. In IL-1 −/− IL-6 −/− hTNFtg mice clinical, as well as, histological signs of disease, including joint inflammation, bone destruction and cartilage damage were also significantly diminished when compared to IL-6 −/− hTNFtg mice. However, by comparing IL-1 −/− IL-6 −/− hTNFtg mice with IL-1 −/− hTNFtg mice the authors found a similar reduction on synovial inflammation, as well as subchondral bone erosions and articular cartilage destruction. Conclusion The phenotype of IL-1 −/− IL-6 −/− hTNFtg mice does not differ from IL-1 −/− hTNFtg animals indicating no synergistic effects when IL-1 and IL-6 is simultaneously blocked in TNF mediated arthritis.

Muscle wasting in hTNFtg mice, an animal model for rheumatoid arthritis, due to increased cathepsin L expression

ObjectiveTo investigate skeletal myopathy in a chronic inflammatory, erosive animal model for rheumatoid arthritis, the human tumour necrosis factor transgenic (hTNFtg) mice.MethodsTo evaluate whether hTNFtg mice are suffering from skeletal...

The signalling domain of the multiadaptor protein p62/SQSTM1 links reactive oxygen species formation and obesity to increased TNFα-mediated joint damage

BackgroundThe multidomain protein p62 plays a key role in signal transduction through interaction with TRAF6, ERK1 and aPKC. It also contributes to protein degradation by autophagy, the ubiquitin proteasome system...

Combined depletion of interleukin 1 and interleukin 6 does not exceed single depletion of interleukin 1 in TNF mediated arthritis

BackgroundPrevious studies demonstrated a regulatory role of interleukin 1 (IL-1) in inflammatory cartilage damage and bone destruction in human tumour necrosis factor transgenic (hTNFtg) mice, an animal model for rheumatoid...

Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis

ObjectiveTo evaluate the role of interleukin 6 (IL-6) in the pathogenesis of bilateral erosive sacroiliitis in human tumour necrosis factor transgenic (hTNFtg) mice, an animal model of ankylosing spondylitis (AS).MethodsHistological...

Interleukin-6 is not a crucial regulator in tumour necrosis factor-mediated bilateral sacroiliitis

To investigate the role of interleukin 6 (IL6) in the pathogenesis of bilateral erosive sacroiliitis in hTNFtg mice, an animal model of ankylosing spondylitis (AS). We crossed IL6−/− mice with...

Aberrant Expression of the Autoantigen Heterogeneous Nuclear Ribonucleoprotein-A2 (RA33) and Spontaneous Formation of Rheumatoid Arthritis-Associated Anti-RA33 Autoantibodies in TNF-α Transgenic Mice

Human TNF-alpha transgenic (hTNFtg) mice develop erosive arthritis closely resembling rheumatoid arthritis (RA). To investigate mechanisms leading to pathological autoimmune reactions in RA, we examined hTNFtg animals for the presence of RA-associated autoantibodies including Abs to citrullinated epitopes (anti-cyclic citrullinated peptide), heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 (anti-RA33), and heat shock proteins (hsp) (anti-hsp). Although IgM anti-hsp Abs were detected in 40% of hTNFtg and control mice, IgG anti-hsp Abs were rarely seen, and anti-cyclic citrullinated peptide Abs were not seen at all. In contrast, >50% of hTNFtg mice showed IgG anti-RA33 autoantibodies, which became detectable shortly after the onset of arthritis. These Abs were predominantly directed to a short epitope, which was identical with an epitope previously described in MRL/lpr mice. Incidence of anti-RA33 was significantly decreased in mice treated with the osteoclast inhibitor osteoprotegerin and also in c-fos-deficient mice lacking osteoclasts. Pronounced expression of hnRNP-A2 and a smaller splice variant was seen in joints of hTNFtg mice, whereas expression was low in control animals. Although the closely related hnRNP-A1 was also overexpressed, autoantibodies to this protein were infrequently detected. Because expression of hnRNP-A2 in thymus, spleen, brain, and lung was similar in hTNFtg and control mice, aberrant expression appeared to be restricted to the inflamed joint. Finally, immunization of hTNFtg mice with recombinant hnRNP-A2 or a peptide harboring the major B cell epitope aggravated arthritis. These findings suggest that overproduction of TNF-alpha leads to aberrant expression of hnRNP-A2 in the rheumatoid joint and subsequently to autoimmune reactions, which may enhance the inflammatory and destructive process.

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-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.