Abstract
ABSTRACTTumor necrosis factor alpha (TNFα) plays a key role in the pathogenesis of rheumatoid arthritis (RA). Blockade of TNFα by monoclonal antibody has been widely used for the therapy of RA since the 1990s; however, its mechanism of efficacy, and potential safety concerns of the treatment are still not fully understood. This study sought to establish a transgenic arthritic mouse model by overexpressing human TNFα (hTNFα) and to apply this model as a means to evaluate therapeutic consequences of TNFα inhibitors. The transgenic mouse line (TgTC) with FVB background was generated by incorporating 3′-modified hTNFα gene sequences. A progressively erosive polyarthritis developed in the TgTC mice, with many characteristics observed in human rheumatoid arthritis, including polyarticular swelling, impairment of movement, synovial hyperplasia, and cartilage and bone erosion. Gene expression analysis demonstrated that hTNFα is not only expressed in hyperplastic synovial membrane, but also in tissues without lesions, including brain, lung and kidney. Treatment of the TgTC mice with anti-hTNFα monoclonal antibodies (mAb) significantly decreased the level of hTNFα in the diseased joint and effectively prevented development of arthritis in a dose-dependent response fashion. Our results indicated that the TgTC mice represent a genetic model which can be used to comprehensively investigate the pathogenesis and therapeutics of TNFα-related diseases.
Highlights
Tumor necrosis factor alpha (TNFα) has a important role in the cascade of pathogenic events in rheumatoid arthritis (McInnes and Schett, 2011)
The mouse line was validated through clinical evaluation, histopathological analysis, transgenic expression and response to anti-human TNFα (hTNFα) treatment
With respect to key clinical features, TgTC mice manifested the symptom of chronic inflammatory polyarthritis after weaning, which is consistent with Tg197 as described (Keffer et al, 1991), but the onset of serious syndrome, such as complete loss of movement of the hind legs, happened around 18–20 weeks compared with 9–10 weeks for Tg197
Summary
Tumor necrosis factor alpha (TNFα) has a important role in the cascade of pathogenic events in rheumatoid arthritis (McInnes and Schett, 2011). High level expression of TNFα in synovium induces joint inflammation and proliferation of fibroblastlike synoviocytes (FLSs). It further triggers cartilage destruction by inducing collagenase expression, inhibits proteoglycan synthesis by articular chondrocytes, and stimulates osteoclastogenesis and bone resorption (Li and Schwarz, 2003). Since the early 1990s, TNFα has become a validated therapeutic target for the treatment of several autoimmune disorders including. Understanding function of TNFα in autoimmune diseases and developing affordable, safe, and potent anti-TNFα analogues is still ongoing worldwide
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