Development of temporomandibular joint arthritis: The use of animal models.

Osteoarthritis is the most common joint disease affecting roughly one sixth of the human population. It is also the most common arthritis affecting the temporomandibular joint, often leading to severe pain and the inability to masticate. Animal models are essential to investigate the disease in part because they lend themselves to genetic manipulation and various treatments and also because of the lack of availability of human specimens from various stages of the disease. The wide range of osteoarthritis models alone are a proof of its multifactorial origin. Manipulation of collagen, cytokine, matrix metalloproteinase and small leucine-rich repeat proteoglycan genes can all have an effect on the development and persistence of arthritis. Surgical models also exist, highlighting the importance of normal anatomy and trauma. Here we review the English literature of murine models of temporomandibular joint arthritis with special attention to the genetic and molecular background of osteoarthritis.

Of mice and men: how animal models advance our understanding of T-cell function in RA.

The involvement of autoreactive T cells in the pathogenesis of rheumatoid arthritis (RA) as well as in autoimmune animal models of arthritis has been well established; however, unanswered questions, such as the role of joint-homing T cells, remain. Animal models of arthritis are superb experimental tools in demonstrating how T cells trigger joint inflammation, and thus can help to further our knowledge of disease mechanisms and potential therapies. In this Review, we discuss the similarities and differences in T-cell subsets and functions between RA and mouse arthritis models. For example, various T-cell subsets are involved in both human and mouse arthritis, but differences might exist in the cytokine regulation and plasticity of these cells. With regard to joint-homing T cells, an abundance of synovial T cells is present in humans compared with mice. On the other hand, local expansion of type 17 T-helper (TH17) cells is observed in some animal models, but not in RA. Finally, whereas T-cell depletion therapy essentially failed in RA, antibody targeting of T cells can work, at least preventatively, in most arthritis models. Clearly, additional human and animal studies are needed to fill the gap in our understanding of the specific contribution of T-cell subsets to arthritis in mice and men.

In vivo two-photon imaging of T cell motility in joint-draining lymph nodes in a mouse model of rheumatoid arthritis.

Recent imaging studies on intact lymph nodes (LNs) of naïve T cell receptor (TCR)-transgenic mice have reported that T cells reduce their motility upon contact with relevant antigen-presenting cells (APCs). Using in vivo two-photon imaging of T cells in joint-draining (JD) LNs, we examined whether similar changes in T cell motility are observed in wild type mice. Co-transfer of T cells from naïve mice and antigen-experienced T cells from mice with proteoglycan (PG)-induced arthritis into naïve or arthritic recipients resulted in prolonged interactions of antigen-experienced T cells with APCs upon intra-articular antigen (PG) injection, indicating that T cells from arthritic wild type mice recapitulate the motile behavior reported in naïve TCR-transgenic mice. However, naïve T cells also engaged in stable interactions with APCs in the JDLNs of arthritic recipients, suggesting an enhanced ability of APCs in the JDLNs of arthritic hosts to present antigen to either naïve or antigen-experienced T cells.

TSG-6 protein, a negative regulator of inflammatory arthritis, forms a ternary complex with murine mast cell tryptases and heparin.

TSG-6 (TNF-α-stimulated gene/protein 6), a hyaluronan (HA)-binding protein, has been implicated in the negative regulation of inflammatory tissue destruction. However, little is known about the tissue/cell-specific expression of TSG-6 in inflammatory processes, due to the lack of appropriate reagents for the detection of this protein in vivo. Here, we report on the development of a highly sensitive detection system and its use in cartilage proteoglycan (aggrecan)-induced arthritis, an autoimmune murine model of rheumatoid arthritis. We found significant correlation between serum concentrations of TSG-6 and arthritis severity throughout the disease process, making TSG-6 a better biomarker of inflammation than any of the other arthritis-related cytokines measured in this study. TSG-6 was present in arthritic joint tissue extracts together with the heavy chains of inter-α-inhibitor (IαI). Whereas TSG-6 was broadly detectable in arthritic synovial tissue, the highest level of TSG-6 was co-localized with tryptases in the heparin-containing secretory granules of mast cells. In vitro, TSG-6 formed complexes with the tryptases murine mast cell protease-6 and -7 via either heparin or HA. In vivo TSG-6-tryptase association could also be detected in arthritic joint extracts by co-immunoprecipitation. TSG-6 has been reported to suppress inflammatory tissue destruction by enhancing the serine protease-inhibitory activity of IαI against plasmin. TSG-6 achieves this by transferring heavy chains from IαI to HA, thus liberating the active bikunin subunit of IαI. Because bikunin is also present in mast cell granules, we propose that TSG-6 can promote inhibition of tryptase activity via a mechanism similar to inhibition of plasmin.