Adenovirus-based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor ? transgenic mice

Schett, Georg; Hayer, Silvia; Tohidast‐Akrad, Makiyeh; Schmid, Beatrice; Lang, Susanne M.; Türk, Birgit; Kainberger, Franz; Haralambous, Sylva; Kollias, George; Newby, Andrew C.; Xu, Qingbo; Steiner, Günter; Smolen, Josef S.

doi:10.1002/1529-0131(200112)44:12<2888::aid-art477>3.0.co;2-3

Cited by 44 publications

(45 citation statements)

References 48 publications

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“…Moreover, A2/RA33 Aab are among the earliest detectable Aab in MRL/lpr lupus mice (80), which, in addition to anti-DNA and other systemic lupus erythematosus-specific Aab, also produce RF and may develop erosive arthritis (81), and have recently been found to occur also in TNF-␣ transgenic mice (Ref. 82 and S. Hayer, B. Jahn-Schmid, D. Plows, K. Skriner, H. Erlandsson-Harris, S. Haralambous, F. Monneaux, S. Trembleau, G. Schett, W. van Venrooij, et al, manuscript in preparation), which represent a well-established model of RA (83). Although the significance of these observations is not yet clear, they may be considered as additional indications for pathogenetic relevance of this autoimmune response.…”

Section: Discussionmentioning

confidence: 71%

Characterization of Autoreactive T Cells to the Autoantigens Heterogeneous Nuclear Ribonucleoprotein A2 (RA33) and Filaggrin in Patients with Rheumatoid Arthritis

Fritsch¹,

Eselböck²,

Skriner³

et al. 2002

The Journal of Immunology

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The role of autoimmune reactions in the pathogenesis of rheumatoid arthritis (RA) is poorly understood. To address this issue we have investigated the spontaneous T cell response to two well-characterized humoral autoantigens in RA patients and controls: 1) the heterogeneous nuclear ribonucleoprotein A2, i.e., the RA33 Ag (A2/RA33), and 2) filaggrin in unmodified and citrullinated forms. In stimulation assays A2/RA33 induced proliferative responses in PBMC of almost 60% of the RA patients but in only 20% of the controls (patients with osteoarthritis or psoriatic arthritis and healthy individuals), with substantially stronger responses in RA patients (p < 0.00002). Furthermore, synovial T cells of seven RA patients investigated were also clearly responsive. In contrast, responses to filaggrin were rarely observed and did not differ between RA patients and controls. Analysis of A2/RA33-induced cytokine secretion revealed high IFN-γ and low IL-4 production in both RA and control PBMC, whereas IL-2 production was mainly observed in RA PBMC (p < 0.03). Moreover, A2/RA33-specific T cell clones from RA patients showed a strong Th1 phenotype and secreted higher amounts of IFN-γ than Th1 clones from controls (p < 0.04). Inhibition experiments performed with mAbs against MHC class II molecules showed A2/RA33-induced T cell responses to be largely HLA-DR restricted. Finally, immunohistochemical analyses revealed pronounced overexpression of A2/RA33 in synovial tissue of RA patients. Taken together, the presence of autoreactive Th1-like cells in RA patients in conjunction with synovial overexpression of A2/RA33 may indicate potential involvement of this autoantigen in the pathogenesis of RA.

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Section: Discussionmentioning

confidence: 71%

Characterization of Autoreactive T Cells to the Autoantigens Heterogeneous Nuclear Ribonucleoprotein A2 (RA33) and Filaggrin in Patients with Rheumatoid Arthritis

Fritsch¹,

Eselböck²,

Skriner³

et al. 2002

The Journal of Immunology

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“…The hTNFtg mouse is considered to be a valuable model of human RA (31,32,40). In these animals, overexpression of hTNF induces severe inflammatory arthritis, which shares many properties with the human counterpart, such as polyarticular involvement of the small joints, chronic and progressive course of disease, and destruction of cartilage and subchondral bone.…”

Section: Discussionmentioning

confidence: 99%

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Schett¹,

Redlich²,

Hayer³

et al. 2003

Arthritis & Rheumatism

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139

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Objective. To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.Methods. We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.Results. Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (؊37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (؊85%) compared with wild-type controls. Osteoclast-covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast-mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNFmediated bone loss by increasing BMD (؉89%) and bone volume (؉647%). Most strikingly, formation of primary spongiosa was dramatically increased (؉563%) in hTNFtg mice after OPG treatment. Osteoclastcovered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast-mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin-1␤ (IL-1␤), and IL-6. However, OPG decreased bone formation parameters (osteoblast-covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti-TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti-TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.Conclusion. OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.

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“…MMP-9, a key MMP in osteoclasts, was also decreased after single and combined treatment with OPG, and MMP-3 expression was also down-regulated by IL-1Ra. These data indicate that inhibition of TNF, IL-1, and RANKL not only reduces the amount of inflamed tissue, but it also affects the molecular composition, and thus the invasive properties, of inflamed tissue, which facilitates destruction of bone and cartilage (5).…”

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confidence: 85%

“…Clinical evaluation was performed weekly, starting at 4 weeks after birth. Arthritis was evaluated in a blinded manner as described previously (5). Briefly, joint swelling was examined in all 4 paws, and a clinical score of 0-3 was assigned (0 ϭ no swelling, 1 ϭ mild, 2 ϭ moderate, and 3 ϭ severe swelling of the toes and ankle).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

“…Studies in animals, such as the human TNF-transgenic (hTNFtg) mouse model, however, suggest that deregulated expression of a single proinflammatory cytokine is sufficient to trigger a complex, progressive, and destructive inflammatory process that closely resembles RA in humans (4). Thus, hTNFtg mice develop an arthritis that shows all 3 pathophysiologic processes that are found in human disease: chronic synovial inflammation, cartilage destruction, and bone erosion (4,5).…”

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confidence: 99%

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Single and combined inhibition of tumor necrosis factor, interleukin‐1, and RANKL pathways in tumor necrosis factor–induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction

Zwerina

Hayer

Tohidast‐Akrad³

et al. 2004

Arthritis & Rheumatism

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293

212

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Objective. To investigate the efficacy of single and combined blockade of tumor necrosis factor (TNF), interleukin-1 (IL-1), and RANKL pathways on synovial inflammation, bone erosion, and cartilage destruction in a TNF-driven arthritis model.Methods. Human TNF-transgenic (hTNFtg) mice were treated with anti-TNF (infliximab), IL-1 receptor antagonist (IL-1Ra; anakinra), or osteoprotegerin (OPG; an OPG-Fc fusion protein), either alone or in combinations of 2 agents or all 3 agents. Synovial inflammation, bone erosion, and cartilage damage were evaluated histologically.Results. Synovial inflammation was inhibited by anti-TNF (-51%), but not by IL-1Ra or OPG monotherapy. The combination of anti-TNF with either IL1Ra (-91%) or OPG (-81%) was additive and almost completely blocked inflammation. Bone erosion was effectively blocked by anti-TNF (-79%) and OPG (-60%), but not by IL-1Ra monotherapy. The combination of anti-TNF with IL-1Ra, however, completely blocked bone erosion (-98%). Inhibition of bone erosion was accompanied by a reduction of osteoclast numbers in synovial tissue. Cartilage destruction was inhibited by anti-TNF (-43%) and was weakly, but not significantly, inhibited by IL-1Ra, but was not inhibited by OPG monotherapy. The combination of anti-TNF with IL-1Ra was the most effective double combination therapy in preventing cartilage destruction (-80%). In all analyses, the triple combination of anti-TNF, IL-1Ra, and OPG was not superior to the double combination of anti-TNF and IL-1Ra.Conclusion. Articular changes caused by chronic overexpression of TNF are not completely blockable by monotherapies that target TNF, IL-1, or RANKL. However, combined approaches, especially the combined blockade of TNF and IL-1 and, to a lesser extent, TNF and RANKL, lead to almost complete remission of disease. Differences in abilities to block synovial inflammation, bone erosion, and cartilage destruction further strengthen the rationale for using combined blockade of more than one proinflammatory pathway.

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Adenovirus-based overexpression of tissue inhibitor of metalloproteinases 1 reduces tissue damage in the joints of tumor necrosis factor ? transgenic mice

Cited by 44 publications

References 48 publications

Characterization of Autoreactive T Cells to the Autoantigens Heterogeneous Nuclear Ribonucleoprotein A2 (RA33) and Filaggrin in Patients with Rheumatoid Arthritis

Characterization of Autoreactive T Cells to the Autoantigens Heterogeneous Nuclear Ribonucleoprotein A2 (RA33) and Filaggrin in Patients with Rheumatoid Arthritis

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Single and combined inhibition of tumor necrosis factor, interleukin‐1, and RANKL pathways in tumor necrosis factor–induced arthritis: Effects on synovial inflammation, bone erosion, and cartilage destruction

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