2023
Clinical Phenotypes of Patients With Systemic Sclerosis With Distinct Molecular Signatures in Skin
Yang M, Goh V, Lee J, Espinoza M, Yuan Y, Carns M, Aren K, Chung L, Khanna D, McMahan ZH, Agrawal R, Nelson L, Shah SJ, Whitfield ML, Hinchcliff M. Clinical Phenotypes of Patients With Systemic Sclerosis With Distinct Molecular Signatures in Skin. Arthritis Care & Research 2023, 75: 1469-1480. PMID: 35997480, PMCID: PMC9947190, DOI: 10.1002/acr.24998.Peer-Reviewed Original ResearchMeSH KeywordsAutoantibodiesFibrosisHumansLung Diseases, InterstitialPhenotypeScleroderma, SystemicSkinConceptsRadiographic interstitial lung diseaseInterstitial lung diseaseHigher mRSSSSc patientsSerum autoantibodiesClinical phenotypeHealthy participantsScl-70 antibodyPresent multicenter studySimilar disease durationSystemic sclerosis patientsDistinct clinical phenotypesSkin gene expressionValuable clinical informationDcSSc patientsDisease durationIdentifies patientsSystemic sclerosisSclerosis patientsMulticenter studyLung diseaseSkin fibrosisSimilar prevalenceClinical dataMultivariable modeling
2022
Epiregulin is a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis
Odell I, Steach H, Gauld S, Reinke-Breen L, Karman J, Carr T, Wetter J, Phillips L, Hinchcliff M, Flavell R. Epiregulin is a dendritic cell–derived EGFR ligand that maintains skin and lung fibrosis. Science Immunology 2022, 7: eabq6691. PMID: 36490328, PMCID: PMC9840167, DOI: 10.1126/sciimmunol.abq6691.Peer-Reviewed Original ResearchConceptsLung fibrosisDendritic cellsImmune cellsDiffuse cutaneous systemic sclerosisPersistence of fibrosisCutaneous systemic sclerosisExtent of fibrosisType I interferonSystemic sclerosisAutoimmune diseasesAntifibrotic targetsTherapeutic administrationMouse modelI interferonLung samplesLung explantsFibrosisFibrotic tissueImmune signalsEpiregulin expressionPatient's skinExtracellular matrix productionGenetic deficiencyEpiregulinEGFR ligandsHuman dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis
Bhandari R, Yang H, Kosarek NN, Smith AE, Garlick JA, Hinchcliff M, Whitfield ML, Pioli PA. Human dermal fibroblast-derived exosomes induce macrophage activation in systemic sclerosis. Rheumatology 2022, 62: si114-si124. PMID: 35946522, PMCID: PMC9910573, DOI: 10.1093/rheumatology/keac453.Peer-Reviewed Original ResearchConceptsFibroblast-derived exosomesSSc patientsMacrophage activationGender-matched control subjectsSSc fibroblastsDonor-derived macrophagesReciprocal activationUpregulated surface expressionMHC class IICo-cultured macrophagesHealthy control fibroblastsExtracellular matrix depositionCell typesSystemic sclerosisHealthy ageIL-10Production of collagenIL-12p40IL-6Control subjectsSkin biopsiesSSc skinTherapeutic targetingClass IIFlow cytometry
2021
Large‐Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis
Bellocchi C, Ying J, Goldmuntz EA, Keyes‐Elstein L, Varga J, Hinchcliff ME, Lyons MA, McSweeney P, Furst DE, Nash R, Crofford LJ, Welch B, Goldin JG, Pinckney A, Mayes MD, Sullivan KM, Assassi S. Large‐Scale Characterization of Systemic Sclerosis Serum Protein Profile: Comparison to Peripheral Blood Cell Transcriptome and Correlations With Skin/Lung Fibrosis. Arthritis & Rheumatology 2021, 73: 660-670. PMID: 33131208, PMCID: PMC8005427, DOI: 10.1002/art.41570.Peer-Reviewed Original ResearchConceptsDiffuse cutaneous systemic sclerosisInterstitial lung diseaseSerum protein profilesHealthy control subjectsControl subjectsSex-matched healthy control subjectsRodnan skin thickness scoreSevere interstitial lung diseaseCutaneous systemic sclerosisMean disease durationDiffuse cutaneous SScWhole blood gene expression profilingSkin thickness scoreBlood gene expression profilingPeripheral blood cellsCancer antigen 15Epidermal growth factor receptorSoluble epidermal growth factor receptorSerum proteinsGrowth factor receptorDisease activityDisease durationSystemic sclerosisCutaneous SScImmunosuppressive agents
2020
Current and Potential New Targets in Systemic Sclerosis Therapy: a New Hope
Hinchcliff M, O’Reilly S. Current and Potential New Targets in Systemic Sclerosis Therapy: a New Hope. Current Rheumatology Reports 2020, 22: 42. PMID: 32562016, PMCID: PMC7305248, DOI: 10.1007/s11926-020-00918-3.Peer-Reviewed Original ResearchConceptsSkin fibrosisNew targetsSSc interstitial lung diseaseAutoimmune connective tissue diseaseSystemic sclerosis therapyConnective tissue diseaseInterstitial lung diseaseCurrent ongoing trialsNew therapeutic targetsActivation of fibroblastsPotential new targetsReviewSystemic sclerosisSclerosis therapyOngoing trialsTissue diseaseLung diseaseClinical trialsTherapeutic targetRate of declineDisease pathogenesisPhase IIIPhase IIFibrosisNew hopeDiseaseProfibrotic Activation of Human Macrophages in Systemic Sclerosis
Bhandari R, Ball MS, Martyanov V, Popovich D, Schaafsma E, Han S, ElTanbouly M, Orzechowski NM, Carns M, Arroyo E, Aren K, Hinchcliff M, Whitfield ML, Pioli PA. Profibrotic Activation of Human Macrophages in Systemic Sclerosis. Arthritis & Rheumatology 2020, 72: 1160-1169. PMID: 32134204, PMCID: PMC7329566, DOI: 10.1002/art.41243.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntigens, CDAntigens, Differentiation, MyelomonocyticCell DifferentiationChemokine CCL2Coculture TechniquesFemaleFibroblastsFibrosisHLA-DR AntigensHumansImmunophenotypingInterleukin-6Lectins, C-TypeLeukocytes, MononuclearMacrophage ActivationMacrophagesMaleMannose ReceptorMannose-Binding LectinsMiddle AgedMonocytesPhosphorylationReceptor, Transforming Growth Factor-beta Type IReceptor, Transforming Growth Factor-beta Type IIReceptors, Cell SurfaceRNA, MessengerScleroderma, SystemicSkinSTAT3 Transcription FactorTranscriptomeTransforming Growth Factor betaConceptsPeripheral blood mononuclear cellsSystemic sclerosisSSc patientsBasal conditionsSex-matched healthy controlsSSc fibroblastsSurface markersHealthy donor monocytesBlood mononuclear cellsMediator of fibrosisInflammatory macrophage activationMonocyte-derived macrophagesActivation profilesGrowth factor βFibrotic activationGene expression signaturesDonor monocytesMononuclear cellsProfibrotic activationSkin fibrosisInterleukin-6Healthy controlsSSc skinIndependent cohortMacrophage activation
2017
Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span
Misharin AV, Morales-Nebreda L, Reyfman PA, Cuda CM, Walter JM, McQuattie-Pimentel AC, Chen CI, Anekalla KR, Joshi N, Williams KJN, Abdala-Valencia H, Yacoub TJ, Chi M, Chiu S, Gonzalez-Gonzalez FJ, Gates K, Lam AP, Nicholson TT, Homan PJ, Soberanes S, Dominguez S, Morgan VK, Saber R, Shaffer A, Hinchcliff M, Marshall SA, Bharat A, Berdnikovs S, Bhorade SM, Bartom ET, Morimoto RI, Balch WE, Sznajder JI, Chandel NS, Mutlu GM, Jain M, Gottardi CJ, Singer BD, Ridge KM, Bagheri N, Shilatifard A, Budinger GRS, Perlman H. Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. Journal Of Experimental Medicine 2017, 214: 2387-2404. PMID: 28694385, PMCID: PMC5551573, DOI: 10.1084/jem.20162152.Peer-Reviewed Original ResearchConceptsMonocyte-derived alveolar macrophagesTissue-resident alveolar macrophagesAlveolar macrophage differentiationMacrophage differentiationTissue-resident macrophagesProfibrotic genesHuman homologueTranscriptomic profilingGenetic deletionAlveolar macrophagesGenesFlow-sorted cellsResolution of fibrosisLife spanDifferentiationHuman alveolar macrophagesSpecific genetic deletionMacrophagesRelative importanceHomologuesA novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis
Taroni JN, Greene CS, Martyanov V, Wood TA, Christmann RB, Farber HW, Lafyatis RA, Denton CP, Hinchcliff ME, Pioli PA, Mahoney JM, Whitfield ML. A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis. Genome Medicine 2017, 9: 27. PMID: 28330499, PMCID: PMC5363043, DOI: 10.1186/s13073-017-0417-1.Peer-Reviewed Original ResearchConceptsDisease-associated signaturesFunctional genomic networksGene expression signaturesPulmonary fibrosisAutoimmune diseasesDisease processMulti-organ autoimmune diseaseDistinct underlying pathologyPro-fibrotic macrophagesInternal organ involvementPulmonary arterial hypertensionExpression signaturesSkin of patientsInnate immune systemWilcoxon rank sum testGenomic networksRank sum testBackgroundSystemic sclerosisArterial hypertensionOrgan involvementSystemic sclerosisUnderlying pathologyLung microenvironmentSkin fibrosisFibrotic genes
2016
Tenascin-C drives persistence of organ fibrosis
Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, Lafyatis R, Lee J, Hinchcliff M, Feghali-Bostwick C, Lakota K, Budinger GR, Raparia K, Tamaki Z, Varga J. Tenascin-C drives persistence of organ fibrosis. Nature Communications 2016, 7: 11703. PMID: 27256716, PMCID: PMC4895803, DOI: 10.1038/ncomms11703.Peer-Reviewed Original ResearchConceptsSystemic sclerosisToll-like receptorsOrgan fibrosisFibrosis resolutionPathogenesis of SScTreatment of SScLevels of tenascinEndogenous danger signalsSSc skin biopsy samplesSkin biopsy samplesMechanism of actionLung fibrosisPathogenic roleTLR activatorsMouse modelBiopsy samplesFibroblast activationDanger signalsMyofibroblast transformationFibrosisSSc fibroblastsCollagen gene expressionSkin fibroblastsAmplification loopTenascin
2014
FibronectinEDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling
Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff M, Hoover P, Getsios S, White ES, Varga J. FibronectinEDA Promotes Chronic Cutaneous Fibrosis Through Toll-Like Receptor Signaling. Science Translational Medicine 2014, 6: 232ra50. PMID: 24739758, PMCID: PMC4414050, DOI: 10.1126/scitranslmed.3008264.Peer-Reviewed Original ResearchConceptsToll-like receptor 4Endogenous TLR4 ligandsCutaneous fibrosisTLR4 ligandToll-like receptor signalingProgressive autoimmune diseaseLesional skin biopsiesFibronectin extra domain ATreatment of fibrosisTissue repair responseHallmark of sclerodermaPersistent fibroblast activationExtra domain ATLR4 blockadeAutoimmune diseasesChronic conditionsChronic fibrosisReceptor 4Skin biopsiesFibrotic responseOrganotypic skin equivalentsMultiple organsPotent stimulusSclerodermaFibroblast activation
2013
Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic Responses
Fang F, Shangguan AJ, Kelly K, Wei J, Gruner K, Ye B, Wang W, Bhattacharyya S, Hinchcliff ME, Tourtellotte WG, Varga J. Early Growth Response 3 (Egr-3) Is Induced by Transforming Growth Factor-β and Regulates Fibrogenic Responses. American Journal Of Pathology 2013, 183: 1197-1208. PMID: 23906810, PMCID: PMC3791870, DOI: 10.1016/j.ajpath.2013.06.016.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsDisease Models, AnimalEarly Growth Response Protein 1Early Growth Response Protein 2Early Growth Response Protein 3FemaleFibroblastsFibrosisGene Expression ProfilingGene Expression RegulationHumansIntracellular SpaceMaleMiceMice, Inbred BALB CMiddle AgedScleroderma, SystemicSignal TransductionSkinSmad ProteinsTransforming Growth Factor betaConceptsEgr-3Genome-wide expression profilingSubstantial functional divergenceEarly growth response (EGR) gene familyEarly growth response 3Egr family membersFunctional divergenceGene familyFibroblast genesGrowth factorTranscription factorsExpression profilingBiological functionsGene expressionDistinct membersEgr familyEgr-1Canonical Smad3Distinct rolesEgr-2Normal skin fibroblastsTissue remodelingFibrotic gene expressionGenesFirst evidenceA synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses
Wei J, Zhu H, Komura K, Lord G, Tomcik M, Wang W, Doniparthi S, Tamaki Z, Hinchcliff M, Distler JH, Varga J. A synthetic PPAR-γ agonist triterpenoid ameliorates experimental fibrosis: PPAR-γ-independent suppression of fibrotic responses. Annals Of The Rheumatic Diseases 2013, 73: 446. PMID: 23515440, PMCID: PMC4028127, DOI: 10.1136/annrheumdis-2012-202716.Peer-Reviewed Original ResearchMeSH KeywordsAdipogenesisAdultAnimalsBiopsyCells, CulturedCollagenDisease Models, AnimalDrug Evaluation, PreclinicalFemaleFibroblastsFibrosisHumansInfant, NewbornMiceMice, Inbred C57BLOleanolic AcidOrgan Culture TechniquesPPAR gammaProto-Oncogene Proteins c-aktScleroderma, SystemicSignal TransductionSkinTransforming Growth Factor betaConceptsSkin organ cultureHuman skin organ cultureAntifibrotic effectsDermal fibrosisExperimental fibrosisOrgan culturePeroxisome proliferator-activated receptor γModulation of fibrogenesisProliferator-activated receptor γHuman skin equivalentsPotential new therapiesPotential therapeutic strategyFibrotic gene expressionSynthetic oleanane triterpenoidComplementary mouse modelsControl of fibrosisPersistent fibroblast activationGrowth factor βTGF-β signalingEffects of CDDOSystemic sclerosisBleomycin injectionFibrogenic responseFibrotic activityMurine model
2012
Wnt/β‐catenin signaling is hyperactivated in systemic sclerosis and induces Smad‐dependent fibrotic responses in mesenchymal cells
Wei J, Fang F, Lam AP, Sargent JL, Hamburg E, Hinchcliff ME, Gottardi CJ, Atit R, Whitfield ML, Varga J. Wnt/β‐catenin signaling is hyperactivated in systemic sclerosis and induces Smad‐dependent fibrotic responses in mesenchymal cells. Arthritis & Rheumatism 2012, 64: 2734-2745. PMID: 22328118, PMCID: PMC3553791, DOI: 10.1002/art.34424.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdultBeta CateninBiopsyCase-Control StudiesCell MovementCell ProliferationCells, CulturedFibroblastsFibrosisFrizzled ReceptorsHumansIntercellular Signaling Peptides and ProteinsLymphoid Enhancer-Binding Factor 1MesodermRepressor ProteinsScleroderma, SystemicSignal TransductionSkinSmad ProteinsWnt ProteinsWnt3A ProteinConceptsWnt/β-cateninCanonical WntWnt-3aMesenchymal cellsGenome-wide expression dataAberrant Wnt/β-catenin pathway activationCell fate specificationΒ-cateninSkin biopsy specimensMyofibroblast differentiationCanonical Wnt/β-cateninWnt/β-catenin signalingWnt receptor Fzd2Subcutaneous preadipocytesSystemic sclerosisΒ-catenin signalingFate specificationBiopsy specimensΒ-catenin activationExpression of WntHuman mesenchymal cellsGrowth factor βPathway componentsGene expressionProfibrotic responsesImatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro.
Hinchcliff M, Huang CC, Ishida W, Fang F, Lee J, Jafari N, Wilkes M, Bhattacharyya S, Leof E, Varga J. Imatinib mesylate causes genome-wide transcriptional changes in systemic sclerosis fibroblasts in vitro. Clinical And Experimental Rheumatology 2012, 30: s86-96. PMID: 22691216, PMCID: PMC3860597.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBiopsyCase-Control StudiesCells, CulturedFibroblastsFibrosisGene Expression ProfilingGene Expression RegulationHumansImatinib MesylateMiceMice, KnockoutOligonucleotide Array Sequence AnalysisPhosphorylationPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesScleroderma, SystemicSignal TransductionSkinTime FactorsTranscription, GeneticTransforming Growth Factor beta1ConceptsSystemic sclerosisSSc fibroblastsSkin biopsiesInternal organ fibrosisHeterogeneous multifactorial diseaseControl fibroblastsControl skin biopsiesFibrotic gene expressionSystemic sclerosis fibroblastsC-AblProgressive skinAntifibrotic effectsImatinib mesylateHealthy controlsCardiovascular diseaseGene expressionHealthy subjectsFibrotic responseCholesterol metabolismOrgan fibrosisC-Abl activationMultifactorial diseaseTreatment resultsTissue levelsFibrosisLevels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker?
Lakota K, Wei J, Carns M, Hinchcliff M, Lee J, Whitfield ML, Sodin-Semrl S, Varga J. Levels of adiponectin, a marker for PPAR-gamma activity, correlate with skin fibrosis in systemic sclerosis: potential utility as biomarker? Arthritis Research & Therapy 2012, 14: r102. PMID: 22548780, PMCID: PMC3446479, DOI: 10.1186/ar3827.Peer-Reviewed Original ResearchConceptsLevels of adiponectinPPAR-gamma activitySerum adiponectin levelsSystemic sclerosisAdiponectin levelsSkin fibrosisSSc patientsSkin scoreDiffuse cutaneous systemic sclerosisPeroxisome proliferator-activated receptor gammaCutaneous systemic sclerosisRodnan skin scoreProliferator-activated receptor gammaHuman subcutaneous preadipocytesProgression of fibrosisAdiponectin mRNA expressionAdiponectin gene expressionTransforming growth factor betaSignificant inverse correlationLongitudinal study changesGrowth factor betaProgressive fibrosisReal-time quantitative PCRAdiponectin expressionHealthy controls
2011
Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma?
Wei J, Melichian D, Komura K, Hinchcliff M, Lam AP, Lafyatis R, Gottardi CJ, MacDougald OA, Varga J. Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: A novel mouse model for scleroderma? Arthritis & Rheumatism 2011, 63: 1707-1717. PMID: 21370225, PMCID: PMC3124699, DOI: 10.1002/art.30312.Peer-Reviewed Original ResearchConceptsSystemic sclerosisSubcutaneous adipose tissueTransgenic miceWnt-10bBiopsy specimensDermal fibrosisMouse modelAdipose tissueLesional skin biopsy specimensSkin biopsy specimensNovel mouse modelMesenchymal cellsSmooth muscle actin gene expressionSkin fibroblastsNovel animal modelFibrotic gene expressionWnt/β-catenin signalingSetting of fibrosisGrowth factor βΒ-catenin signalingPulmonary fibrosisSubcutaneous lipoatrophySkin fibrosisGene expressionMyofibroblast accumulation
2009
A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate
Bhattacharyya S, Ishida W, Wu M, Wilkes M, Mori Y, Hinchcliff M, Leof E, Varga J. A non-Smad mechanism of fibroblast activation by transforming growth factor-β via c-Abl and Egr-1: selective modulation by imatinib mesylate. Oncogene 2009, 28: 1285-1297. PMID: 19151753, PMCID: PMC4006376, DOI: 10.1038/onc.2008.479.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzamidesBleomycinCells, CulturedCollagenEarly Growth Response Protein 1Extracellular Signal-Regulated MAP KinasesFibroblastsFibrosisHumansImatinib MesylateMiceMice, Inbred BALB CNIH 3T3 CellsPiperazinesProtein Kinase InhibitorsProto-Oncogene Proteins c-ablPyrimidinesSignal TransductionSmad2 ProteinSmad3 ProteinTransforming Growth Factor betaConceptsChronic myelogenous leukemiaFibrotic responseEgr-1Growth factorUpregulated tissue expressionFibrosis of skinNovel therapeutic approachesEarly growth response factor-1Kinase-deficient mutant formC-AblNormal fibroblastsTGF-β stimulationIntracellular signaling mechanismLesional skinStimulation of collagenImatinib mesylateMouse embryonic fibroblastsFibrotic processMyelogenous leukemiaTherapeutic approachesPharmacological targetingTarget of inhibitionTGF-β responseFibroblast activationC-Abl activation
2007
Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness
Mori Y, Hinchcliff M, Wu M, Warner-Blankenship M, Lyons K, Varga J. Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness. Experimental Cell Research 2007, 314: 1094-1104. PMID: 18201696, PMCID: PMC3963386, DOI: 10.1016/j.yexcr.2007.12.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell ProliferationCells, CulturedCollagenCollagen Type IConnective Tissue Growth FactorEmbryo, MammalianExtracellular MatrixFibroblastsFibrosisGene ExpressionImmediate-Early ProteinsIntercellular Signaling Peptides and ProteinsMiceSignal TransductionSmad ProteinsTransforming Growth Factor betaConceptsEmbryonic fibroblastsSmad-dependent transcriptional responsesTGF-beta signal transductionMatricellular protein connective tissue growth factorMurine embryonic fibroblastsMouse embryonic fibroblastsProtein connective tissue growth factorWild-type MEFsTransient transfection assaysMyofibroblast transdifferentiationCCN2 expressionRegulation of proliferationCorresponding protein levelsCCN2 functionsCollagen gene expressionTranscriptional responseRT-PCR analysisLoss of CCN2Signal transductionEndogenous CCN2Transfection assaysExtracellular matrix synthesisMouse embryosGene expressionWild type