Expression of sphingosine kinase 2 in synovial fibroblasts of rheumatoid arthritis contributing to apoptosis by a sphingosine analogue, FTY720

Abstract

Gene expression profiles in synovial tissues from rheumatoid arthritis (RA) patients have yielded useful information on the pathogenetic process of the synovitis. In one group of them, sphingosine kinase 2 (SPHK2), a nuclear protein regulating cell proliferation, seemed to be highly expressed, undergoing a different pathogenetic process of synovitis. In the present study it was clarified that SPHK2 was expressed in the synovial fibroblasts of the synovial tissues obtained from the knee joints of the RA patients. In the cultured synovial fibroblasts from these patients, SPHK2 was more highly expressed than that in the human macrophage cell line, THP‐1 and human dermal fibroblasts. SPHK2 was expressed in and around the nucleus and transferred to the cytoplasm and cell surface by the administration of epidermal growth factor, associated with the increased expression of sphingosine‐1‐phosphate. A sphingosine analogue, FTY720, which is activated by phosphorylation specifically by SPHK2, mediated apoptotic signaling of the cultured synovial fibroblasts. These findings suggest that SPHK2 may regulate the autonomous proliferation of synovial fibroblasts as one of the predisposing genes to RA and could be a target for a novel therapeutic strategy for RA.

Targeting the Metabolism and Receptors of Sphingosine-1- Phosphate for the Treatment of Rheumatoid Arthritis

“…Increased SphK1 expression and activity were found in RA B lymphoblastoid cell lines, which were implicated as the underlying mechanism of impaired Fas-mediated death signalling in RA (Pi et al, 2006). More recently, SphK2 was shown to be expressed in rheumatoid synovial fibroblasts in vivo and in vitro and associated with the up-regulation of S1P production (Kamada et al, 2009). Surprisingly, FTY-720 (2-amino-2-[2-(4-octylphenyl) ethyl] propane-1, 3-diol hydrochloride), a sphingosine analog that is phosphorylated to the active metabolite FTY-720-phosphate (FTY-720-P) by SphK2 (Brinkmann et al, 2002;Mandala et al, 2002), induces apoptosis of synovial fibroblasts.…”

“…The role played by S1P in the autoimmune disease rheumatoid arthritis (RA) has recently emerged. Activated SphK and elevated levels of S1P have been detected in the synovium and synovial fluids of patients with RA, respectively (Kamada et al, 2009;Kitano et al, 2006;Lai et al, 2008). In addition, exogenously applied S1P in cultured synovial fibroblasts from RA patients causes cell migration, production of cytokines/chemokines, expression of cyclooxygenase-2 and prostaglandins, as well as cell proliferation and survival (Kitano et al, 2006;Zhao et al, 2008).…”

Apoptosis Resistance in Rheumatoid Arthritis Synovial Tissue

“…In a recent study, SPHK2 was shown to be abundantly present in and around the nucleus of RASF and SPHK2 was successfully transferred from the nucleus to the cytoplasm after treating RASF with epidermal growth factor [81]. In addition, the sphingosine analogue, FTY720 was activated by SPHK2 and this activation step induced apoptosis in RASF.…”

Sphingosine-1-Phosphate and Rheumatoid Arthritis: Pathological Implications and Potential Therapeutic Targets

“…TNF-α can activate SphK, which leads to the production of S1P [46]. Indeed, SphK1, SphK2 [3,47] and S1P levels [48] are elevated in the synovium of patients with RA. Moreover, administration of S1P to RA synovial fibroblasts causes their proliferation, survival, and migration, as well as cytokine/ chemokine and other proinflammatory mediator production [4,5].…”

“…Accumulating evidence now suggests a role for S1P in various as-pects of RA biology. This can involve, for example, activation of SphKs [3] and an elevated level of S1P [4] in the synovium and synovial fluids of patients with RA, as well as alterations in S1P signalling that lead to synovial fibroblast migration, proliferation, survival and production of proinflammatory cytokines/chemokines [4,5]. This review will highlight how S1P is involved in RA pathology and the mechanisms of its action.…”