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  • br ATX LPA pathway in animal models of rheumatoid arthritis

    2024-02-23


    ATX–LPA pathway in animal models of rheumatoid arthritis Several animal models have been used to characterize the mechanisms involved in the pathogenesis of arthritis and to test new therapeutic strategies. The collagen-induced arthritis (CIA) model (Courtenay et al., 1980, Luross and Williams, 2001, Hegen et al., 2008), the K/BxN model (Kouskoff et al., 1996, Kouskoff et al., 1997) and TNF transgenic mice (Keffer et al., 1991) are the most used animal models. In the CIA model, DBA/1 mice with the MHC Class II I-Aq haplotype develop arthritis after injection with type-II collagen in complete Freund's adjuvant. The initial injection is followed by an intraperitoneal collagen booster 21 days later. This model allows the study of the two phases in the development of arthritis. The initial autoimmune response involves the production of collagen-specific T and B cells. The subsequent AZD2014 phase is characterized by joint inflammation, cartilage damage and bone erosion. The disease severity peaks at day 35 and the incidence and severity of the disease depends on mice maintenance conditions and environment (Courtenay et al., 1980, Hegen et al., 2008). In the K/BxN arthritis model described by Kouskoff et al., a T cell receptor (TCR) transgene recognises glucose-6-phosphate isomerase presented in the context of the MHC class-II molecule I-Ag7. The immune reaction induces an early and rapidly progressive arthritis that is T- and B-cell dependant and is similar to human RA. The serum from these mice causes arthritis in a wide range of recipient strains because of high levels of autoantibodies against the glucose-6-phosphate isomerase (GPI) and represents the K/BxN serum-transfer model. This model allows the study of the mechanisms and molecules involved in the effector phase of arthritis independent of the initial autoimmune response (Kouskoff et al., 1997). The TNF transgenic mouse reported by Keffer et al. (1991) was the first model of spontaneous arthritis. These mice overexpress human TNF and spontaneously develop an erosive chronic poly-arthritis that closely mimics human RA. The mice develop synovial hyperplasia, pannus formation, cartilage destruction and bone erosion. This model established the fundamental role of TNF in the pathogenesis of RA. Recently, these three models have been used by several research groups to analyse the involvement of the ATX–LPA pathway in experimental arthritis models (Table 1). In the first of these studies, Nikitopoulou et al. analysed the TNF transgenic and the CIA models in FLS lacking ATX by conditional ablation. The authors showed that in the two models the absence of ATX reduced the clinical severity of arthritis and the synovial inflammation and hyperplasia using a histopathological analysis of joints. More recently, Orosa et al. analysed the effect of lysophosphatidic acid receptor inhibition in the K/BxN serum-transfer arthritis model. In this work, mice were injected with K/BxN serum and treated with the LPA1/3 antagonist, Ki16425. This treatment attenuated the clinical severity of arthritis and reduced synovial inflammation, cartilage damage and bone erosion in joints from arthritic mice. These findings were accompanied by increased apoptosis and the reduced production of inflammatory mediators in joints. Interestingly, the marked decrease of bone erosion was the result of reduced osteoclast differentiation and function with increased differentiation of osteoblasts and bone mineralisation (Orosa et al., 2014). Furthermore, Miyabe et al. (2013) reported that LPA1 deficient mice were protected from arthritis after immunisation with type II collagen. The histopathological analysis of joints showed an absence of synovial inflammation, cartilage damage and bone erosion. Interestingly, the authors found interplay between the LPA1 receptor and Th17 cells as differentiation of these cells was abrogated in mice lacking LPA1 (Miyabe et al., 2013). This study also reported the reduction of osteoclast differentiation in LPA1 deficient mice, which is consistent with findings from Orosa et al. Thus, it seems clear that ATX–LPA signalling pathway plays a direct role in osteoclast differentiation. Additional evidence supporting this role comes from studies in other fields as the study of David et al. reporting that expression of ATX controls the progression of osteolytic bone metastasis in mice and that LPA increases osteoclast formation in response to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kB ligand (RANK-L) (David et al. 2010). Furthermore, Lapierre et al. (2010) have recently reported that LPA increases osteoclast survival.