Genetic Sphingosine Kinase 1 Deficiency Significantly Decreases Synovial Inflammation and Joint Erosions in Murine TNF-α–Induced Arthritis

Abstract

Sphingosine kinase 1 (SphK1) is an enzyme that converts sphingosine to bioactive sphingosine-1-phosphate. Recent in vitro data suggest a potential role of SphK1 in TNF-α–mediated inflammation. Our aims in this study were to determine the in vivo significance of SphK1 in TNF-α–mediated chronic inflammation and to define which pathogenic mechanisms induced by TNF-α are SphK1 dependent. To pursue these aims, we studied the effect of SphK1 deficiency in an in vivo model of TNF-α–induced chronic inflammatory arthritis. Transgenic hTNF-α mice, which develop spontaneous inflammatory erosive arthritis beginning at 14–16 wk, were crossed with SphK1 null mice (SphK1−/−), on the C57BL6 genetic background. Beginning at 4 mo of age, hTNF/SphK1−/− mice had significantly less severe clinically evident paw swelling and deformity, less synovial and periarticular inflammation, and markedly decreased bone erosions as measured quantitatively through micro-CT images. Mechanistically, the mice lacking SphK1 had less articular cyclooxygenase 2 protein and fewer synovial Th17 cells than did hTNF/SphK1+/+ littermates. Microarray analysis and real-time RT-PCR of the ankle synovial tissue demonstrated that hTNF/SphK1−/− mice had increased transcript levels of suppressor of cytokine signaling 3 compared with hTNF/SphK1+/+ mice, likely also contributing to the decreased inflammation in the SphK1-deficient mice. Finally, significantly fewer mature osteoclasts were detected in the ankle joints of hTNF/SphK1−/− mice compared with hTNF/SphK1+/+ mice. These data indicate that SphK1 plays a key role in hTNF-α–induced inflammatory arthritis via impacting synovial inflammation and osteoclast number.