**4.1 Rheumatoid arthritis**

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joint synovium, synovial hyperplasia and a massive infiltration of inflammatory cells into the affected joints, leading to the progressive destruction of cartilage and bone (Feldmann et al., 1996a). The inciting agent that triggers the development of RA is unknown; however, the disease is clearly an inflammatory process since the critical events in RA are largely coordinated by complex interplays of proinflammatory cytokines, chemokines, and matrix metalloproteinases produced by both synovial resident cells and infiltrating cells (Feldmann et al., 1996b; McInnes and Schett, 2007). These inflammatory mediators are involved in many pathological processes in RA. Increasing evidence demonstrates,

Fig. 2. S1P metabolism and signalling in RA synoviocytes. A range of agonists including growth factors, hormones, angiogenic factors and other stimuli activate SphKs through phosphorylation. S1P is then generated and exported out of the cells by ABC transporters to act on the same cell (autocrine) or on nearby cells (paracrine). S1P engages with its receptors (S1P1-3) to mediate a diverse array of signalling pathways, impacting fundamental biological processes that are integral to the pathogenesis of RA, such as cell proliferation and survival, cell migration, and inflammatory mediator secretion.

regulates stomatal aperture (Coursol et al., 2005) or stress responses and survival (Jenkins and Hannun, 2001), respectively. Similarly, in mammalian cells intracellular S1P regulates calcium release independently of inositol trisphosphate formation and of S1P receptor activation (Blom et al., 2005). S1P also signals within the nucleus by binding to and inhibiting histone deacetylases HDAC1 and HDAC2, leading to the epigenetic regulation of gene expression (Hait et al., 2009). Further studies are needed, however, to reveal the

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joint synovium, synovial hyperplasia and a massive infiltration of inflammatory cells into the affected joints, leading to the progressive destruction of cartilage and bone (Feldmann et al., 1996a). The inciting agent that triggers the development of RA is unknown; however, the disease is clearly an inflammatory process since the critical events in RA are largely coordinated by complex interplays of proinflammatory cytokines, chemokines, and matrix metalloproteinases produced by both synovial resident cells and infiltrating cells (Feldmann et al., 1996b; McInnes and Schett, 2007). These inflammatory mediators are

involved in many pathological processes in RA. Increasing evidence demonstrates,

Fig. 2. S1P metabolism and signalling in RA synoviocytes. A range of agonists including growth factors, hormones, angiogenic factors and other stimuli activate SphKs through phosphorylation. S1P is then generated and exported out of the cells by ABC transporters to act on the same cell (autocrine) or on nearby cells (paracrine). S1P engages with its receptors

biological processes that are integral to the pathogenesis of RA, such as cell proliferation and

(S1P1-3) to mediate a diverse array of signalling pathways, impacting fundamental

survival, cell migration, and inflammatory mediator secretion.

intracellular second messenger functions of S1P.

**4.1 Rheumatoid arthritis** 

**4. Role of SphK/S1P/S1PR signalling in rheumatoid arthritis** 

however, that the activation of RA synoviocytes can be maintained in the absence of inflammatory cytokines (Muller-Ladner et al., 1996), indicating the involvement of biologically active mediators other than inflammatory cytokines in RA disease progression. Emerging evidence suggests a role for S1P metabolism and signalling in various aspects of the pathogenesis of RA. Recent *in vitro* and *in vivo* studies evaluated the potential role of S1P synthesis, catabolism enzymes and S1P signalling in RA (Fig. 2).
