Elucidating the Role of Sulfatase-2 in RA Pathogenesis
Elucidating the Role of Sulfatase-2 in RA Pathogenesis
批准号:
10402717
负责人:
Ruby J. Siegel
金额:
$1.23万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-16 至 2021-12-15
关键词:
AdhesionsAffectAnti-Inflammatory AgentsAnti-Tumor Necrosis Factor TherapyApoptosisArthritisAutomobile DrivingCX3CL1 geneCXCL10 geneCXCL11 geneCartilageCell Adhesion MoleculesCell ProliferationCell surfaceChronicCleaved cellClinical TrialsComplexDataDiseaseEconomic BurdenEffectivenessEndothelial CellsEnzymesEstersExhibitsFibroblastsGenesGrowth FactorHeparan Sulfate ProteoglycanHeparitin SulfateHumanHyperplasiaIL8 geneIn VitroIncidenceInflammationInflammation MediatorsInflammatoryIntercellular adhesion molecule 1Interleukin-6JointsLigand BindingMediatingMediator of activation proteinMolecularPathogenesisPathway AnalysisPathway interactionsPatientsPatternPharmacological TreatmentPharmacologyPhenotypePlayProductionProteinsRANTESRNA analysisResistanceRheumatoid ArthritisRoleSafetySeveritiesSignal PathwaySignal TransductionSmall Interfering RNAStromal CellsSulfatasesSulfateSynovial MembraneTNF geneTNFRSF1A geneTestingTherapeuticTissuesTransgenic MiceVascular Cell Adhesion Molecule-1Vascular Endothelial Growth Factorsangiogenesisarthropathiesbonecadherin-11cell typechemokinecommon treatmentconventional therapycytokinedisabilityeffectiveness testingextracellulargain of functiongene inductionin vivo evaluationknock-downloss of functionmacrophagemigrationmouse modelnovelosteoclastogenesisreceptorsmall molecule inhibitorsocioeconomicssuccesstherapeutic targettranscriptometranscriptome sequencing
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
In rheumatoid arthritis (RA), the cytokine tumor necrosis factor-α (TNF-α) plays a dominant role in driving synovial
hyperplasia and progressive destruction of cartilage and bone. Our preliminary data suggests the extracellular
enzyme Sulfatase-2 (Sulf-2) to be a potential mediator (or facilitator) of TNF-α signaling in RA synovial fibroblasts
(RASFs). At the cell surface, Sulf-2 cleaves sulfate groups from heparan sulfate proteoglycans (HSPGs), which
in turn affects the receptor/ligand binding and subsequent signaling of an array of chemokines, cytokines and
growth factors. Interactions between TNF-α and HSPGs are not well defined, and the role of Sulf-2 in TNF-α
signaling remains unexplored. We found that inhibition of Sulf-2 in human RASFs with siRNA or a small molecule
inhibitor (OKN-007) significantly reduced TNF-α-induced expression of adhesion molecules ICAM-1, VCAM-1
and Cadherin-11, and production of inflammatory mediators IL-6 and IL-8. Transcriptome analysis by RNA
sequencing (RNAseq) showed that, compared to a negative control siRNA, knockdown of Sulf-2 significantly
reduced TNF-α induction of genes related to adhesion, cell proliferation, and chemokines, while concomitantly
increasing expression of bone-protective and anti-inflammatory genes. Pathway analysis of RNASeq results
showed that Sulf-2 knockdown in TNF-α-stimulated RASFs significantly altered expression of 48 genes in the
top canonical pathway Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis. This
proposal capitalizes on these novel observations, and the central hypothesis of our study is that Sulf-2 mediates
TNF-α signaling to promote synovial hyperplasia, invasion and tissue destruction in RA. As an extracellular
enzyme, Sulf-2 is an attractive target for pharmacologic inhibition, and a small molecule inhibitor of Sulf-2 has
shown high biosafety in human clinical trials. We aim to elucidate the mechanism of Sulf-2 participation in TNF-
α signaling and investigate the potential therapeutic value of targeting Sulf-2-dependent pathways for the
treatment of RA. Studies proposed in Aim 1 will investigate the molecular mechanisms of Sulf-2 modulation of
TNF-α signaling pathways and effects on downstream mediators of pathogenesis in human RASFs. In Aim 2 we
will test the in vivo effects of pharmacologic inhibition of Sulf-2 in a human TNF-α transgenic mouse model of
RA. The success of these studies will reveal a novel molecular mechanism of modulating TNF-α signaling in
RASFs by regulating Sulf-2, and validate the safety and effectiveness of a potential new pharmacologic treatment
for this common and debilitating disease.
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