Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNFα single-chain Fv antibody (ESBA105) designed for local therapeutic use

Urech, David; Feige, Ulrich; Ewert, Stefan; Schlosser, Viola; Ottiger, Michael; Polzer, K; Schett, Georg; Lichtlen, Peter

doi:10.1136/ard.2008.105775

Cited by 59 publications

(49 citation statements)

References 45 publications

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“…Such an alteration is primarily associated with the complex network of interactions among inflammatory factors, resulting in synovial inflammation and chondrocytic disturbance (18,19). As one of the key inflammatory factors responsible for the articular cartilage degeneration, TNF-· is involved in the synovial inflammatory response, the initiation of chondrocytic apoptosis, the imbalance between chondral damage and repairs and the eventual acceleration of articular cartilage degeneration (20). In order to study the effects of millimeter wave treatment on TNF-·-induced cell death, we established chondrocyte culture in vitro by using stepwise 0.2% collagenase type II digestion and then we treated the chondrocytes with 0, 10, 20 and 40 ng/ml TNF-· for 2, 4 and 8 h. As expected, we found an evident decreasing trend in the activities of chondrocytes by MTT assay with time and TNF-· dosage.…”

Section: Discussionmentioning

confidence: 99%

In vitro study of inhibitory millimeter wave treatment effects on the TNF-α-induced NF-κB signal transduction pathway

Wu²,

Wu³

et al. 2010

Int J Mol Med

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Abstract. Abnormal activation of the nuclear factor-κB (NF-κB) in chondrocytes initiates the transcription of inflammatory mediators, promotes their generation and release, and amplifies initial inflammatory signals. This results in the release of chondral matrix-degrading enzymes and accelerates the degeneration of articular cartilage. As a non-pharmaceutical and non-invasive physical therapy regimen, millimeter wave treatment has been successfully used for the treatment of osteoarthritis. In this study, chondrocytes were derived from the cartilages of knee joints of 4-week-old male Sprague-Dawley rats and were mechanically digested by collagenase type II treatment for further culture in vitro. The third-passage chondrocytes were stained with toluidine blue and treated with a gradient of tumor necrosis factor-· (TNF-·) for various times. Chondrocytic activity was measured by MTT assay, and the apoptotic rate of the chondrocytes was determined with Hocehst 33342 staining to identify effective treatment concentrations and durations and to establish an apoptosis model for the chondrocytes in response to TNF-·. Using this model, the chondrocytes were randomly divided to receive millimeter wave treatment for various times. The apoptotic rate of the chondrocytes was measured by Annexin V-FITC staining and the protein expression levels of RIP, TAK1, IκB kinase (IKK)-ß, IκB-· and NF-κB, were determined by Western blotting. Chondrocytic structure was examined by transmission electronic microscopy. The apoptotic rates were significantly lower at 4 and 8 h of treatment than at 0 and 2 h. The expression levels of RIP, TAK1, IKK-ß and NF-κB were also significantly lower at 4 and 8 h than at 0 and 2 h, whereas that of IκB-· was significantly higher at 4 and 8 h than at 0 and 2 h. Therefore, we can conclude that millimeter wave treatment can inhibit the activation of the TNF-·-mediated NF-κB signal transduction pathway through the down-regulation of RIP, TAK1, IKK-ß and NF-κB, and the up-regulation of IκB-·, in chondrocytes.

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Section: Discussionmentioning

confidence: 99%

In vitro study of inhibitory millimeter wave treatment effects on the TNF-α-induced NF-κB signal transduction pathway

Wu²,

Wu³

et al. 2010

Int J Mol Med

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“…The grades were summed to obtain an arthritis index (ranging from 0 to 8) (21). TB-stained slides were used to estimate joint proteoglycan content, as described previously (22). Images of the joint surface of each sample were digitalized and evaluated using Image J software (National Institutes of Health, Bethesda, MD).…”

Section: Knee Joint Evaluationmentioning

confidence: 99%

Experimental Arthritis Triggers Periodontal Disease in Mice: Involvement of TNF-α and the Oral Microbiota

Queiroz-Junior

Madeira

Coelho

et al. 2011

The Journal of Immunology

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Rheumatoid arthritis (RA) and periodontal disease (PD) are prevalent chronic inflammatory disorders that affect bone structures. Individuals with RA are more likely to experience PD, but how disease in joints could induce PD remains unknown. This study aimed to experimentally mimic clinical parameters of RA-induced PD and to provide mechanistic findings to explain this association. Chronic Ag-induced arthritis (AIA) was triggered by injection of methylated BSA in the knee joint of immunized mice. Anti–TNF-α was used to assess the role of this cytokine. Intra-articular challenge induced infiltration of cells, synovial hyperplasia, bone resorption, proteoglycan loss, and increased expression of cytokines exclusively in challenged joints. Simultaneously, AIA resulted in severe alveolar bone loss, migration of osteoclasts, and release of proinflammatory cytokines in maxillae. Anti–TNF-α therapy prevented the development of both AIA and PD. AIA did not modify bacterial counts in the oral cavity. PD, but not AIA, induced by injection of Ag in immunized mice was decreased by local treatment with antiseptic, which decreased the oral microbiota. AIA was associated with an increase in serum C-reactive protein levels and the expression of the transcription factors RORγ and Foxp3 in cervical lymph nodes. There were higher titers of anti-collagen I IgG, and splenocytes were more responsive to collagen I in AIA mice. In conclusion, AIA-induced PD was dependent on TNF-α and the oral microbiota. Moreover, PD was associated with changes in expression of lymphocyte transcription factors, presence of anti-collagen Abs, and increased reactivity to autoantigens.

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“…Changlong Y et al found that NF-B p65-speciWc siRNA inhibited the expression of COX-2, NOS-2, and MMP-9 induced by TNF in vitro and in vivo research [13,14]. However, they didn't pay attention to whether the chondrocytes or synovial cells exerted apoptosis 2 weeks after stimulation.…”

Section: Discussionmentioning

confidence: 97%

“…Because of the important role of TNF in OA, there were dozens of studies targeting inhibition of TNF trying to slow down or halt disease progression. They indeed yielded some beneWts on relieving articular swelling and inhibiting cartilage damage triggered by TNF in the rat model [14]. Nuclear factor-kappa B (NF-B), one of the TNF downstream factors, was also considered as an OA therapy target and down-regulated to relieve articular inXammation and bone erosion [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

TNFα-mediated apoptosis in human osteoarthritic chondrocytes sensitized by PI3K-NF-κB inhibitor, not mTOR inhibitor

Duan

et al. 2011

Rheumatol Int

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To investigate apoptosis of osteoarthritic (OA) chondrocytes stimulated with different inhibitors targeting tumor necrosis factor-alpha (TNFα) pathway, we isolated first passage chondrocytes from OA patients and then treated them with the inhibitors in combination with TNFα, and then collected the stimulated chondrocytes for Western blotting. Chondrocytes from OA patients expressed cleaved caspase-3 and PARP, suggesting apoptotic background. We here, validated that 10 ng/ml of TNFα couldn't induce more chondrocytes apoptosis. PI3K inhibitor LY294002 or NF-κB inhibitor CAPE, but not mTOR inhibitor rapamycin and MEK1/2 inhibitor U0126 in combination with TNFα could facilitate apoptosis. CAPE-induced more apoptosis could be explained by c-FLIP downregulation more than cIAP1 upregulation. And, we showed the first time that PI3K-NF-κB pathway, but not mTOR pathway could prevent chondrocytes apoptosis induced by a pro-apoptotic factor TNFα and call for attention while trying to inhibit NF-κB as a therapeutic target.

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Anti-inflammatory and cartilage-protecting effects of an intra-articularly injected anti-TNFα single-chain Fv antibody (ESBA105) designed for local therapeutic use

Abstract: ESBA105 potently inhibits inflammation and prevents cartilage damage triggered by TNFalpha. In contrast to a full length IgG, ESBA105 also penetrates into cartilage and can be expected to reverse the TNFalpha-induced catabolic state of articular cartilage in arthritides.

Cited by 59 publications

References 45 publications

In vitro study of inhibitory millimeter wave treatment effects on the TNF-α-induced NF-κB signal transduction pathway

In vitro study of inhibitory millimeter wave treatment effects on the TNF-α-induced NF-κB signal transduction pathway

Experimental Arthritis Triggers Periodontal Disease in Mice: Involvement of TNF-α and the Oral Microbiota

TNFα-mediated apoptosis in human osteoarthritic chondrocytes sensitized by PI3K-NF-κB inhibitor, not mTOR inhibitor

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