LPA binds to six specific

LPA binds to six specific cell surface GPCR receptors. The receptors LPA1 (lysophosphatidic receptor 1, formerly, Edg2), LPA2 (Edg4) and LPA3 (Edg7) belong to the endothelial differentiation gene family (EDG) and share sequence homology (50–60% amino 3,4-DAA homology) An et al., 1997, An et al., 1998, Bandoh et al. (1999), Tokumura et al. (2002). LPA4 (formerly, GPR23/P2Y9) (Noguchi et al., 2003), LPA5 (GPR92) (Lee et al., 2006) and LPA6 (P2Y5) (Pasternack et al., 2008) are more dissimilar and closely related to P2Y nucleotide receptors. Furthermore, PPARγ has been identified as an intracellular receptor for LPA (McIntyre et al., 2003). After binding to its receptor, LPA activates several signalling pathways through coupling to the G-proteins Gi/o, Gq/11 and G12/13 depending on the cell type. The interaction with Gi/o protein leads to the inhibition of adenylate cyclase and activation of phosphatidylinositol 3-kinase/Akt and Ras/MAPK pathways. The interaction with Gq/11 activates phospholipase C and protein kinase C, whereas LPA coupled to G12/13 leads to the activation of RhoA GTPase (Noguchi et al., 2003; Lee et al., 2006; Van Meeteren and Moolenaar, 2007; Umezu-Goto et al., 2004a, Umezu-Goto et al., 2004b). By controlling these pathways, LPA is able to regulate several cellular processes, including survival, proliferation, differentiation and motility (Van Meeteren and Moolenaar, 2007). In addition, the ATX–LPA pathway is involved in the growth and metastasis of different tumours (Umezu-Goto et al., 2004a, Umezu-Goto et al., 2004b, Gotoh et al., 2012) and in other pathological disorders, such as pulmonary, dermal and renal fibrosis (Pradère et al., 2007, Johnson and Lapadat, 2002).
ATX–LPA pathway in rheumatoid arthritis In RA, the synovial membrane becomes hyperplastic due to the proliferation of resident macrophages and FLS and the subsequent infiltration of circulating cells, such as T cells, B cells, monocytes, natural-killer cells, neutrophils, plasma cells and mast cells (Feldmann et al., 1996, Firestein, 2003, Klareskog et al., 2009). Resident FLS play an active role in synovial inflammation and damage. They secrete a plethora of cytokines and chemokines that perpetuate a state of chronic inflammation and produce matrix-remodelling enzymes, such as matrix metalloproteinases (MMPs), agrecanases and cathepsins that contribute to joint destruction. The production of these inflammatory factors is mediated by signal transduction pathways, such as the mitogen-activated protein kinase (MAPK) signalling pathway, which includes c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38 MAPK (Inoue et al., 2006, Schett et al., 2008). All three phosphorylated forms of MAPK have been detected in RA synovium and cultured FLS (Schett et al., 2008, Thalhamer et al., 2008). The involvement of the ATX–LPA pathway in the pathogenesis of rheumatoid arthritis was initially suggested by Santos et al. (1996). In this work, the authors described the presence of ATX mRNA in FLS from RA patients and its downregulation by IFN-γ. The same group later performed a comparative analysis and found that levels of ATX mRNA in FLS from RA patients were 5-fold higher than non-RA patients (Kehlen et al., 2001). A recent study from Aidinis' group confirmed the presence of ATX in FLS from RA patients and reported that this expression was higher in FLS adjacent to damaged cartilage (Nikitopoulou et al., 2012). Furthermore, Miyabe et al. recently showed a higher ATX expression in RA synovium compared with OA synovium. In addition, two research groups demonstrated the presence of ATX protein in synovial fluid from RA patients (Nochi et al., 2008, Zhao et al., 2008). In the study of Nochi et al., the authors found that the ATX substrate LPC was also present in synovial fluid from RA patients. Collectively, these findings suggest that ATX could be involved in the pathogenesis of rheumatoid arthritis by inducing local production of LPA in the synovium and synovial fluid from LPC. However, infiltrating cells in synovium such as T cells, neutrophils and monocytes could contribute to the increase of LPA in synovial fluid and synovium of RA patients because LPA can be also produced intracellularly by hydrolysis of phosphatidic acid (PA) by cytosolic phospholipases.