title: Genetic sphingosine kinase 1 deficiency significantly decreases synovial inflammation and joint erosions in murine TNF-alpha-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-alpha-mediated inflammation. Our aims in this study were to determine the in vivo significance of SphK1 in TNF-alpha-mediated chronic inflammation and to define which pathogenic mechanisms induced by TNF-alpha are SphK1 dependent. To pursue these aims, we studied the effect of SphK1 deficiency in an in vivo model of TNF-alpha-induced chronic inflammatory arthritis. Transgenic hTNF-alpha 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-alpha-induced inflammatory arthritis via impacting synovial inflammation and osteoclast number.
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: DeAnna A
authors.initials: DA
authors.lastname: Baker
authors.forename: Jeremy
authors.initials: J
authors.lastname: Barth
authors.forename: Raymond
authors.initials: R
authors.lastname: Chang
authors.forename: Lina M
authors.initials: LM
authors.lastname: Obeid
authors.forename: Gary S
authors.initials: GS
authors.lastname: Gilkeson
mesh_terms: D000818:Animals; D000843:Ankle Joint / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001168:Arthritis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D033023:Foot Joints / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007596:Joints / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D013585:Synovitis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000099157:Sphingosine Kinase
chemical_list: D051546:Cyclooxygenase 2; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013107:Sphingolipids; D013110:Sphingosine; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C491411:Socs3 protein, mouse; C060506:sphingosine 1-phosphate; C077623:Ptgs2 protein, mouse