Potential role of sphingosine 1-phosphate in the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis is a chronic, destructive, autoimmune joint disease that affects one to two million Americans (or approximately 1% of the population of the United States). This disease can strike at any age and affects roughly three times as many women as men (http://ww2. arthritis.org/conditions/DiseaseCenter/RA/ra_who.asp). Symptoms include joint stiffness, swelling, and pain, as well as systemic effects associated with inflammation; and indeed, anti-inflammatory drugs are a mainstay of treatment (http://my.clevelandclinic.org/disorders/rheumatoid_ arthritis/hic_what_drugs_are_used_to_treat_rheumatoid_ arthritis.aspx). However, newer biologics that target the cytokine tumor necrosis factor-a (TNFa) have demonstrated efficacy, suggesting the importance of this agent in rheumatoid arthritis. Nevertheless, partial responses and nonresponses suggest that TNFa is not the sole mediator, and additional cytokines and chemokines are being sought as targets for the development of treatments for rheumatoid arthritis (as reviewed in Ref. 1). Rheumatoid arthritis is characterized by inflammation of the lining of the joints, the synovium, followed by destruction of the cartilage and bone within the joint and invasion into these tissues of the rheumatoid pannus. The pannus is a hyperplastic, inflammatory tissue consisting largely of T, B, and dendritic cells and macrophages, constituting an immune compartment, and synovial fibroblasts, or fibroblast-like synoviocytes, comprising an erosive compartment (as reviewed in Ref. 2). These fibroblast-like synoviocytes also produce a number of growth factors, such as platelet-derived growth factor, fibroblast growth factor, vascular endothelial growth factor, and epidermal growth factor, and proinflammatory agents including interleukins (IL) -1-b, -6, -8, -11, -15, and -16, TNFa, transforming growth factor-b, prostaglandin E2, and receptor activator of nuclear factor-kB ligand (RANKL) (as reviewed in Ref. 2). RANKL may be critically involved in the erosion of bone in rheumatoid arthritis, because this agent induces differentiation of macrophages into bonedestroying osteoclasts (as reviewed in Refs. 2, 3), whereas the cytokines are probably key to inflammation and the growth factors important for the observed pannus hyperplasia. The mechanisms mediating this hyperplasia are unknown but may involve both increased proliferation and/or improved survival (i.e., decreased apoptosis) of fibroblast-like synoviocytes (as reviewed in Ref. 3). In the article by Zhao et al. (4) reported in this issue, Bourgoin and colleagues identify another possible mediator of synoviocyte migration (invasion), survival, and cytokine production, i.e., sphingosine 1-phosphate (S1P). These investigators show that fibroblast-like synoviocytes express three of the five known S1P receptors, S1P1, S1P2, and S1P3, and that S1P or S1P agonists induce cell migration and secretion of IL-6 and -8 and reduce apoptosis. The S1P receptors mediating these processes were determined using receptor-selective agonists and antagonists, and the results are summarized in Table 1. Interestingly, these authors did not detect an effect of S1P on synoviocyte proliferation, although a previous study demonstrated a small effect of S1P on proliferation in synoviocytes of rheumatoid arthritis patients (5). As discussed by Zhao et al. (4), in this prior investigation, S1Pʼs effects on proliferation were examined in the presence of 10% serum; thus, the difference may lie in the fact that whereas S1P by itself may not be sufficient to trigger proliferation, it may act synergistically with a component or components of serum to elicit synoviocyte growth. Nevertheless, the ability of S1P to promote fibroblast-like synoviocyte survival, whether or not this agent can also increase cell proliferation, could contribute to pannus hyperplasia (3). This article by Zhao et al. (4) also examines the mechanisms underlying S1Pʼs effects on synoviocytes. Using inhibitors of the various pathways, the authors find that S1P increases migration through activation of extracellular signal-regulated kinase-1 and -2 (ERK-1/2), as well as p38 and Rho kinase, a downstream effector of the small GTPase Rho. These three pathways also mediate S1Pʼs regulation of cytokine production, although the involvement of ERK-1/2 in this cellular response is minor.