, Volume 19, Issue 2, pp 75–87 | Cite as

Attenuation of arthritis in rodents by a novel orally-available inhibitor of sphingosine kinase

  • Leo R. FitzpatrickEmail author
  • Cecelia Green
  • Elizabeth E. Frauenhoffer
  • Kevin J. French
  • Yan Zhuang
  • Lynn W. Maines
  • John J. Upson
  • Emmanuel Paul
  • Henry Donahue
  • Timothy J. Mosher
  • Charles D. Smith
Research Article


Pro-inflammatory cytokines like TNF-α activate sphingosine kinase (SK). Therefore, inhibition of SK is a potential molecular target for the treatment of rheumatoid arthritis.


The primary goal of this study was to assess the efficacy of ABC249640 (a selective SK-2 inhibitor) in two models of rodent arthritis. A secondary goal was to evaluate the pharmacological profile of ABC294640, when given in combination with methotrexate.


The efficacy of ABC294640 was determined by paw diameter/volume measurements, histological evaluations, and micro-CT analyses.


ABC294640 attenuated both collagen-induced arthritis in mice, as well as adjuvant-induced arthritis in rats. With the adjuvant arthritis model, the prophylactic efficacy profile of ABC294640 was similar to indomethacin. Of note, ABC294640 reduced the bone and cartilage degradation, associated with adjuvant-induced arthritis. Rats treated with a suboptimal dose of MTX (50 μg/kg/day) in combination with ABC249640 (100 mg/kg/day) had better anti-arthritis effects in the adjuvant model, than treatment with either agent alone.


Our results suggest that ABC249640 is an orally available drug candidate with a good pre-clinical efficacy profile for the prevention and/or treatment of RA.


Sphingosine kinase Arthritis Rodents ABC-294640 


  1. Anthony DD, Haqqi TM (1999) Collagen-induced arthritis in mice: an animal model to study the pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 17:240–244PubMedGoogle Scholar
  2. Brand DD (2005) Rodent models of rheumatoid arthritis. Comp Med 55:114–122PubMedGoogle Scholar
  3. Feely MG, Erickson A, O’Dell JR (2009) Therapeutic options for rheumatoid arthritis. Expert Opin Pharmacother 10:2095–2106PubMedCrossRefGoogle Scholar
  4. French KJ, Schrecengost B, Lee BD et al (2003) Discovery and evaluation of inhibitors of human sphingosine kinase. Cancer Res 63:5962–5969PubMedGoogle Scholar
  5. French KJ, Upson JJ, Keller SN et al (2006) Antitumor activity of sphingosine kinase inhibitors. JPET 318:596–603CrossRefGoogle Scholar
  6. French KJ, Zhuang Y, Maines LW et al (2010) Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. JPET 333:129–139CrossRefGoogle Scholar
  7. Goldring MB (1999) The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models. Connect Tissue Res 40:1–11PubMedCrossRefGoogle Scholar
  8. Griffiths RJ, Pettipher ER, Koch K et al (1995) Leukotriene B4 plays a critical role in the progression of collagen-induced arthritis. Proc Natl Acad Sci USA 92:517–521PubMedCrossRefGoogle Scholar
  9. Gugasyan R, Clouston D, Mandel T et al (1997) Prevention of splenic granuloma formation in adjuvant arthritis by n2-acetyl-4-tetrahydroxybutylimidazole (THI). Immunol Lett 58:133–138PubMedCrossRefGoogle Scholar
  10. Hamada T, Arima N, Shindo M et al (2000) Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase inhibitor. Br J Pharmacol 131:1513–1520PubMedCrossRefGoogle Scholar
  11. Hegen M, Sun L, Uozumi N et al (2003) Cytosolic phospholipase A2 alpha-deficient mice are resistant to collagen-induced arthritis. J Exp Med 197:1297–1302PubMedCrossRefGoogle Scholar
  12. Hegen M, Keith JC, Collins M et al (2008) Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis 67:1505–1515PubMedCrossRefGoogle Scholar
  13. Holmdahl R, Bockerman R, Bavklund J et al (2002) The molecular pathogenesis of collagen-induced arthritis in mice-a model for rheumatoid arthritis. Ageing Res Rev 1:135–147PubMedCrossRefGoogle Scholar
  14. Kannan K, Otrmann RA, Kimpl D (2005) Animal models of rheumatoid arthritis and their relevance to human disease. Pathophysiology 12:167–181PubMedCrossRefGoogle Scholar
  15. Kato S, Ogawa Y, Kanatu K et al (2002) Ulcerogenic influence of selective cyclooxygenase inhibitors in the rat stomach with adjuvant-induced arthritis. JPET 303:503–509CrossRefGoogle Scholar
  16. Kee TH, Vit P, Melendez AJ (2005) Sphingosine kinase in immune cells. Clin Exp Pharmacol Physiol 32:153–161PubMedCrossRefGoogle Scholar
  17. Keohane CA, Mandala S, Spiegel S et al (2004) Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 279:52487–52492PubMedCrossRefGoogle Scholar
  18. Lai WQ, Irwan AW, Goh HH et al (2008) Anti-inflammatory effects of sphingosine kinase modulation in inflammatory arthritis. J Immunol 181:8010–8017PubMedGoogle Scholar
  19. Lai WQ, Irwan AW, Goh HH (2009) Distinct roles of sphingosine kinase 1 and 2 in murine collagen-induced arthritis. J Immunol 183:2097–2103PubMedCrossRefGoogle Scholar
  20. Luross JA, Heaton T, Hirst TR et al (2002) Escherichia coli heat- labile enterotoxin B subunit prevents autoimmune arthritis through induction of regulatory CD4+ T cells. Arthritis Rheum 46:1671–1682PubMedCrossRefGoogle Scholar
  21. MacKinnon AC, Buckley A, Chilvers ER et al (2002) Sphingosine kinase: a point of convergence in the action of diverse neutrophil priming agents. J Immunol 169:6394–6400PubMedGoogle Scholar
  22. Magari K, Miyata S, Fusako N et al (2003) Differential effects of FK506 and methotrexate on inflammatory cytokine levels in rat adjuvant-induced arthritis. J Rheumatol 30:2193–2200PubMedGoogle Scholar
  23. Maines LW, French KJ, Wolpert EB et al (2006) Pharmacological manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases. Invest Opthamol Vis Sci 47:5022–5031CrossRefGoogle Scholar
  24. Maines LW, Fitzpatrick LR, French KJ et al (2008) Suppression of ulcerative colitis in mice by orally available inhibitors of sphingosine kinase. Dig Dis Sci 53:997–1012PubMedCrossRefGoogle Scholar
  25. Maines LW, Fitzpatrick LR, Green CL et al (2010) Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease. Inflammopharmacology [PMID:2015210]Google Scholar
  26. Matsukawa A, Yoshinaga M (1998) Sequential generation of cytokines during the initiative phase of inflammation, with reference to neutrophils. Inflamm Res 47(Suppl 3):S137–S144PubMedCrossRefGoogle Scholar
  27. Michaud J, Kohno M, Proia RL et al (2006) Normal acute and chronic inflammatory responses in sphingosine kinase 1 knockout mice. FEBS Lett 580:4607–4612PubMedCrossRefGoogle Scholar
  28. Ochi T, Goto T (2002) Differential effect of FR122047, a selective cyclo-oxygenase-1 inhibitor, in rat chronic models of arthritis. Br J Pharmacol 135:782–788PubMedCrossRefGoogle Scholar
  29. Oliver SJ, Brain E (1996) Combination therapy in rheumatoid arthritis: the animal model perspective. J Rheumatol 23(Suppl 4):56–60Google Scholar
  30. Olivera A, Spiegel S (2001) Sphingosine kinase: a mediator of vital cellular functions. Prostaglandins Other Lipid Mediat 64:123–134PubMedCrossRefGoogle Scholar
  31. Pendley CE, Fitzpatrick LR, Ewing RW et al (1993) The gastrin/cholecystokinin-B receptor antagonist reduces basal acid secretion and prevents gastrointestinal damage by aspirin, ethanol and cysteamine in the rat. JPET 265:1348–1354Google Scholar
  32. Pettus BJ, Bielawski J, Porcelli AM et al (2003) The sphingosine kinase 1/sphingosine-1-phosphate pathway mediates COX-2 induction and PGE2 production in response to TNF-alpha. Faseb J 17:1411–1421PubMedCrossRefGoogle Scholar
  33. Saito H, Kojima T, Takahashi M et al (2007) A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as antitumor-necrosis factor-monoclonal antibody in murine collagen-induced arthritis. Arthritis Rheum 56:1164–1174PubMedCrossRefGoogle Scholar
  34. Schopf LR, Anderson K, Jeffee BD (2006) Rat models of arthritis: similarities, differences, advantages and disadvantages in the identification of novel therapeutics. In: Stevenson CS, Marshall LA, Morgan DW (eds) in vivo models of inflammation, vol 1. Birkhauser Verlag, Boston, USA, pp 1–34Google Scholar
  35. Smith CD, French KJ, Zhuang Y (2008) Sphingosine kinase inhibitors. US Patent Number 7,338,961Google Scholar
  36. Taha TA, Hannun YA, Obedi LM (2006) Sphingosine kinase: biochemical and cellular regulation and role in disease. J Biochem Mol Bio 39:113–131Google Scholar
  37. Wessels JAM, Huizings TWJ, Guchelaar HJ (2008) Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology 47:249–255PubMedCrossRefGoogle Scholar
  38. Xia P, Gamble JR, Trye KA et al (1998) Tumor necrosis factor-alpha induces adhesion molecule expression through the sphingosine kinase pathway. Proc Natl Acad Sci USA 95:14196–14201PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Leo R. Fitzpatrick
    • 1
    Email author
  • Cecelia Green
    • 2
  • Elizabeth E. Frauenhoffer
    • 4
  • Kevin J. French
    • 2
  • Yan Zhuang
    • 2
  • Lynn W. Maines
    • 2
  • John J. Upson
    • 2
  • Emmanuel Paul
    • 5
  • Henry Donahue
    • 5
  • Timothy J. Mosher
    • 6
  • Charles D. Smith
    • 2
    • 3
  1. 1.Department of PharmacologyPenn State College of MedicineHershey, HummelstownUSA
  2. 2.Apogee Biotechnology CorporationHersheyUSA
  3. 3.Department of Pharmaceutical SciencesMedical University of South CarolinaCharlestonUSA
  4. 4.Department of PathologyPenn State College of MedicineHersheyUSA
  5. 5.Department of OrthopaedicsPenn State College of MedicineHersheyUSA
  6. 6.Department of RadiologyPenn State College of MedicineHersheyUSA

Personalised recommendations