Featured Publications
PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases
Zhao X, Lin Y, Liou B, Fu W, Jian J, Fannin V, Zhang W, Setchell K, Grabowski G, Sun Y, Liu C. PGRN deficiency exacerbates, whereas a brain penetrant PGRN derivative protects, GBA1 mutation-associated pathologies and diseases. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 120: e2210442120. PMID: 36574647, PMCID: PMC9910439, DOI: 10.1073/pnas.2210442120.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainGaucher DiseaseGlucosylceramidaseLysosomesMiceMice, KnockoutMutationParkinson DiseaseProgranulinsConceptsBlood-brain barrierParkinson's diseaseGaucher diseasePGRN deficiencyPD-like phenotypesRelevant mouse modelRare lysosomal storage diseaseCommon neurodegenerative disorderVisceral symptomsNeurobehavioral deficitsSevere neuroinflammationPD pathologyLysosomal storage diseaseTherapeutic studiesMouse modelNeuronopathic involvementProgranulinImpaired autophagyNeurodegenerative disordersGD phenotypeEarly onsetMiceDiseaseFirst linePathologyTNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity
Fu W, Hu W, Yi Y, Hettinghouse A, Sun G, Bi Y, He W, Zhang L, Gao G, Liu J, Toyo-oka K, Xiao G, Solit D, Loke P, Liu C. TNFR2/14-3-3ε signaling complex instructs macrophage plasticity in inflammation and autoimmunity. Journal Of Clinical Investigation 2021, 131 PMID: 34185706, PMCID: PMC8363273, DOI: 10.1172/jci144016.Peer-Reviewed Original ResearchConceptsMacrophage polarizationMacrophage plasticityPI3K/Akt/mTORPathogenesis of inflammationMyeloid-specific deletionNF-κB activationAkt/mTORInflammatory arthritisAntiinflammatory pathwayImmunoregulatory roleAutoimmune diseasesProtective effectTherapeutic implicationsInflammationTNFR2 signalingAutoimmunityTNFR2TNFR2 activationReceptor complexDiseaseIntracellular regulatorsActivationMolecule 14TNFR1Arthritis14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis
Fu W, Hettinghouse A, Chen Y, Hu W, Ding X, Chen M, Ding Y, Mundra J, Song W, Liu R, Yi Y, Attur M, Samuels J, Strauss E, Leucht P, Schwarzkopf R, Liu C. 14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis. Annals Of The Rheumatic Diseases 2021, 80: 1615-1627. PMID: 34226187, PMCID: PMC8595573, DOI: 10.1136/annrheumdis-2021-220000.Peer-Reviewed Original ResearchConceptsPathogenesis of osteoarthritisTNFR2 complexTherapeutic effectSingle-cell RNA-seqIntracellular componentsReceptor complexExtracellular signal-regulated kinaseNuclear factor kappa BSignal-regulated kinaseCommon joint diseaseFactor kappa BChondrocyte-specific deletionProteomic screenElk-1RNA-seqTranscription factorsCell-based assaysTNF signalingTNFR2 pathwayInducible componentJoint diseaseActivity screenTherapeutic targetKappa BOsteoarthritisADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis
Lai Y, Bai X, Zhao Y, Tian Q, Liu B, Lin E, Chen Y, Lee B, Appleton C, Beier F, Yu X, Liu C. ADAMTS-7 forms a positive feedback loop with TNF-α in the pathogenesis of osteoarthritis. Annals Of The Rheumatic Diseases 2013, 73: 1575. PMID: 23928557, PMCID: PMC4418017, DOI: 10.1136/annrheumdis-2013-203561.Peer-Reviewed Original ResearchConceptsADAMTS-7ADAMTS-7 expressionRat OA modelPathogenesis of osteoarthritisNF-κB signalingOA modelOA progressionCartilage degradationOA-like phenotypeTumor necrosis factorProgression of osteoarthritisJoint degenerative diseaseDownstream NF-κB signalingPotential molecular targetsPositive feedback loopShort-limbed dwarfismDisease progressionOA developmentNecrosis factorSafranin O stainingYoung miceUpregulated TNFReporter gene assayOsteoarthritisTransgenic miceThe Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice
Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, Syed NM, Lai Y, Lin EA, Kong L, Su J, Yin F, Ding AH, Zanin-Zhorov A, Dustin ML, Tao J, Craft J, Yin Z, Feng JQ, Abramson SB, Yu XP, Liu CJ. The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice. Science 2011, 332: 478-484. PMID: 21393509, PMCID: PMC3104397, DOI: 10.1126/science.1199214.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAnimalsAnti-Inflammatory Agents, Non-SteroidalArthritis, ExperimentalCartilage, ArticularFemaleGranulinsHumansIntercellular Signaling Peptides and ProteinsLigandsMaleMiceMice, Inbred StrainsMice, KnockoutMice, TransgenicMiddle AgedProgranulinsProtein Interaction Domains and MotifsReceptors, Tumor Necrosis Factor, Type IReceptors, Tumor Necrosis Factor, Type IIRecombinant Fusion ProteinsRecombinant ProteinsSignal TransductionT-Lymphocytes, RegulatoryTumor Necrosis Factor-alphaYoung AdultConceptsInflammatory arthritisAdministration of progranulinAntagonist of TNFαCollagen-induced arthritisArthritis mouse modelPGRN-deficient miceNew potential therapeutic interventionsPotential therapeutic interventionsGrowth factor progranulinNecrosis factor receptorRheumatoid arthritisMouse modelArthritisTherapeutic interventionsProgranulinTNF receptorFactor receptorMiceReceptorsInflammationTissue repairTNFαIntracellular signalingAtsttrinTNFRProgranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease
Jian J, Tian Q, Hettinghouse A, Zhao S, Liu H, Wei J, Grunig G, Zhang W, Setchell K, Sun Y, Overkleeft H, Chan G, Liu C. Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease. EBioMedicine 2016, 13: 212-224. PMID: 27789271, PMCID: PMC5264254, DOI: 10.1016/j.ebiom.2016.10.010.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineDisease Models, AnimalFibroblastsGaucher DiseaseGlucosylceramidaseHSP70 Heat-Shock ProteinsHumansIntercellular Signaling Peptides and ProteinsLysosome-Associated Membrane GlycoproteinsLysosomesMiceMice, KnockoutPhenotypeProgranulinsProtein AggregatesProtein BindingRecombinant ProteinsStress, PhysiologicalConceptsGaucher diseaseLysosomal storage diseaseStorage diseaseCommon lysosomal storage diseaseNew therapeutic interventionsΒ-glucocerebrosidaseProgranulin insufficiencyAnimal modelsTherapeutic interventionsDiseasePGRNDisease phenotypePatient fibroblastsGCaseComplex-associated proteinsLysosomal localizationHSP70DeficiencyAssociation Between Progranulin and Gaucher Disease
Jian J, Zhao S, Tian QY, Liu H, Zhao Y, Chen WC, Grunig G, Torres PA, Wang BC, Zeng B, Pastores G, Tang W, Sun Y, Grabowski GA, Kong MX, Wang G, Chen Y, Liang F, Overkleeft HS, Saunders-Pullman R, Chan GL, Liu CJ. Association Between Progranulin and Gaucher Disease. EBioMedicine 2016, 11: 127-137. PMID: 27515686, PMCID: PMC5049935, DOI: 10.1016/j.ebiom.2016.08.004.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAllelesAnimalsCase-Control StudiesDisease Models, AnimalEnzyme ActivationFemaleGaucher DiseaseGene FrequencyGenetic Association StudiesGenotypeHumansIntercellular Signaling Peptides and ProteinsLysosomesMaleMiceMice, KnockoutMiddle AgedMutationPhenotypePolymorphism, Single NucleotideProgranulinsProtein TransportConceptsGD patientsHealthy controlsGaucher diseaseGRN genePGRN KO miceSerum PGRN levelsPGRN-deficient miceHealthy control samplesSerum levelsPGRN levelsGaucher-like cellsKO miceTherapeutic effectRecombinant PGRNGeneral populationPatientsAnimal modelsBone marrowGBA1 geneLysosomal localizationProgranulin geneNull micePGRNDiseaseMice
2021
Progranulin associates with Rab2 and is involved in autophagosome-lysosome fusion in Gaucher disease
Zhao X, Liberti R, Jian J, Fu W, Hettinghouse A, Sun Y, Liu C. Progranulin associates with Rab2 and is involved in autophagosome-lysosome fusion in Gaucher disease. Journal Of Molecular Medicine 2021, 99: 1639-1654. PMID: 34453183, PMCID: PMC8541919, DOI: 10.1007/s00109-021-02127-6.Peer-Reviewed Original ResearchConceptsLysosomal storage diseaseGaucher diseaseAutophagosome-lysosome fusionCommon lysosomal storage diseasePGRN deficiencyNovel therapiesAnimal modelsProgranulinLC3-IIMolecular targetsCrucial mediatorCritical moleculesStorage diseaseDiseaseAutophagic fluxC-terminal fragmentImpaired fusionPatient fibroblastsAutophagyImpairmentKey regulator
2019
Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice
Wang C, Zhang L, Ndong J, Hettinghouse A, Sun G, Chen C, Zhang C, Liu R, Liu C. Progranulin deficiency exacerbates spinal cord injury by promoting neuroinflammation and cell apoptosis in mice. Journal Of Neuroinflammation 2019, 16: 238. PMID: 31775776, PMCID: PMC6882111, DOI: 10.1186/s12974-019-1630-1.Peer-Reviewed Original ResearchConceptsBasso Mouse ScaleNeurological recoverySpinal cord injuryCord injuryWestern blottingWild-type littermate miceMacrophages/microgliaPromising therapeutic approachWeight-drop techniqueNew therapeutic targetsHuge economic burdenPro-apoptotic effectsPLGA thermosensitive hydrogelFunctional recoveryPGRN deficiencyPGRN expressionLittermate miceIntrathecal spaceProgranulin deficiencyTherapeutic approachesTherapeutic targetEconomic burdenWT controlsDay 21Day 7
2018
Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease
Chen Y, Jian J, Hettinghouse A, Zhao X, Setchell K, Sun Y, Liu C. Progranulin associates with hexosaminidase A and ameliorates GM2 ganglioside accumulation and lysosomal storage in Tay-Sachs disease. Journal Of Molecular Medicine 2018, 96: 1359-1373. PMID: 30341570, PMCID: PMC6240367, DOI: 10.1007/s00109-018-1703-0.Peer-Reviewed Original ResearchRole of ADAMTS‐12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor
Wei J, Fu W, Hettinghouse A, He W, Lipson K, Liu C. Role of ADAMTS‐12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor. Arthritis & Rheumatology 2018, 70: 1745-1756. PMID: 29750395, PMCID: PMC6203634, DOI: 10.1002/art.40552.Peer-Reviewed Original ResearchConceptsConnective tissue growth factorCIA mouse modelADAMTS-12Inflammatory arthritisTissue growth factorMouse modelCollagen-induced arthritis modelGrowth factorRheumatoid arthritis developmentEnzyme-linked immunosorbentRA patientsArthritis developmentPannus formationSerum levelsCartilage destructionArthritis modelInflammatory cytokinesEnhanced osteoclastogenesisHealthy subjectsArthritisAnkle jointTomography scanningInflammationSusceptibility genesCritical regulatorEstablishment of a Modified Collagen-Induced Arthritis Mouse Model to Investigate the Anti-inflammatory Activity of Progranulin in Inflammatory Arthritis
Wei J, Liu C. Establishment of a Modified Collagen-Induced Arthritis Mouse Model to Investigate the Anti-inflammatory Activity of Progranulin in Inflammatory Arthritis. Methods In Molecular Biology 2018, 1806: 305-313. PMID: 29956284, DOI: 10.1007/978-1-4939-8559-3_20.Peer-Reviewed Original ResearchConceptsChicken type II collagenArthritis mouse modelPGRN-deficient miceInflammatory arthritisAnti-inflammatory activityMouse modelDeficient miceCollagen-Induced Arthritis Mouse ModelProtective roleCollagen-induced arthritis (CIA) mouse modelAutoimmune inflammatory arthritisHuman rheumatoid arthritisAutoimmune modelComplete Freund'sRheumatoid arthritisDegenerative arthritisPathological featuresDegenerative osteoarthritisControl littermatesCIA modelArthritisHigh incidenceType II collagenProgranulinDisease modelsp204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice
Yi Y, Jian J, Gonzalez-Gugel E, Shi Y, Tian Q, Fu W, Hettinghouse A, Song W, Liu R, He M, Qi H, Yang J, Du X, Xiao G, Chen L, Liu C. p204 Is Required for Canonical Lipopolysaccharide-induced TLR4 Signaling in Mice. EBioMedicine 2018, 29: 78-91. PMID: 29472103, PMCID: PMC5925582, DOI: 10.1016/j.ebiom.2018.02.012.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedCytokinesGenotypeImmunity, InnateInflammasomesInflammation MediatorsInterferon Regulatory Factor-3Interferon-betaLipopolysaccharidesMacrophage ActivationMacrophagesMiceMice, KnockoutModels, BiologicalNF-kappa BNuclear ProteinsPhosphoproteinsProtein BindingProtein MultimerizationRAW 264.7 CellsShock, SepticSignal TransductionToll-Like Receptor 4ConceptsPro-inflammatory cytokinesLPS challengeIRF-3 pathwayDimerization of TLR4Serum levelsLPS-TLR4TLR4 signalingNF-ĸBAnimal modelsPyrin domainInnate immunityExtracellular LPSInterferon-inducible p200 familyInfectious diseasesLPSMicePotential targetTLR4IFNCytokinesMacrophagesBacterial DNASignificant defectsDramatic reductionPathwayChitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease
Jian J, Chen Y, Liberti R, Fu W, Hu W, Saunders-Pullman R, Pastores G, Chen Y, Sun Y, Grabowski G, Liu C. Chitinase-3-like Protein 1: A Progranulin Downstream Molecule and Potential Biomarker for Gaucher Disease. EBioMedicine 2018, 28: 251-260. PMID: 29396296, PMCID: PMC5835567, DOI: 10.1016/j.ebiom.2018.01.022.Peer-Reviewed Original ResearchConceptsGD patientsHealthy controlsGaucher diseaseDownstream moleculesExpression of CHI3L1Serum CHI3L1Serum levelsPGRN levelsTherapeutic effectClinical biomarkersPatientsPotential biomarkersNull miceCHI3L1ProgranulinElevated levelsBiomarkersWhole-genome microarraysDiseaseCHIT1Genome microarraysNovel regulatorImmunohistochemistryLevelsMice
2017
Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models
Wei J, Fu W, Ding Y, Hettinghouse A, Lendhey M, Schwarzkopf R, Kennedy O, Liu C. Progranulin derivative Atsttrin protects against early osteoarthritis in mouse and rat models. Arthritis Research & Therapy 2017, 19: 280. PMID: 29258611, PMCID: PMC5735869, DOI: 10.1186/s13075-017-1485-8.Peer-Reviewed Original ResearchConceptsTherapeutic effectOA modelPain-related markersAnti-catabolic effectsRole of progranulinDegenerative joint diseaseMurine OA modelMultiple murine modelsNew therapeutic alternativesTumor necrosis factor receptorIntra-articular deliveryNecrosis factor receptorInflammatory arthritisPGRN deficiencyOA phenotypeSafranin O stainingTherapeutic alternativeRat modelJoint diseaseOsteoarthritis progressionPreventative effectMurine modelCartilage degradationDegenerative factorsEarly osteoarthritis
2016
Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner
Mundra J, Jian J, Bhagat P, Liu C. Progranulin inhibits expression and release of chemokines CXCL9 and CXCL10 in a TNFR1 dependent manner. Scientific Reports 2016, 6: 21115. PMID: 26892362, PMCID: PMC4759551, DOI: 10.1038/srep21115.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCD4-Positive T-LymphocytesChemokine CXCL10Chemokine CXCL9Cluster AnalysisDermatitis, ContactGene Expression ProfilingGene Expression RegulationIntercellular Signaling Peptides and ProteinsMacrophagesMiceMice, KnockoutProgranulinsReceptors, Tumor Necrosis Factor, Type IRecombinant ProteinsConceptsWild-type B6 micePGRN KO miceRecombinant PGRN proteinTNFR1-dependent mannerSeverity of inflammationInflammatory bowel diseaseAnti-inflammatory functionalityCXCL9 expressionTreg populationGene array analysisBowel diseaseDermatitis modelRheumatoid arthritisChemokine expressionChemokines CXCL9Autoimmune diseasesB6 micePGRN functionCXCL10 expressionKO miceT cellsPleiotrophic growth factorsImmune systemProgranulinNull mice
2010
Granulin epithelin precursor: a bone morphogenic protein 2‐inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis
Feng J, Guo F, Jiang B, Zhang Y, Frenkel S, Wang D, Tang W, Xie Y, Liu C. Granulin epithelin precursor: a bone morphogenic protein 2‐inducible growth factor that activates Erk1/2 signaling and JunB transcription factor in chondrogenesis. The FASEB Journal 2010, 24: 1879-1892. PMID: 20124436, PMCID: PMC2874481, DOI: 10.1096/fj.09-144659.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBiomarkersBlotting, WesternBone Morphogenetic Protein 2CartilageCell DifferentiationCells, CulturedChondrocytesChondrogenesisChromatin ImmunoprecipitationFetusGene Expression ProfilingHumansImmunoenzyme TechniquesIn Situ HybridizationIntercellular Signaling Peptides and ProteinsMesenchymal Stem CellsMiceMice, Inbred C3HMice, KnockoutMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Oligonucleotide Array Sequence AnalysisProgranulinsProto-Oncogene Proteins c-junRabbitsReverse Transcriptase Polymerase Chain ReactionRNA ProbesRNA, MessengerSignal TransductionConceptsJunB transcription factorKey downstream moleculeGranulin-epithelin precursorChondrocyte differentiationTranscription factorsDownstream moleculesNovel critical roleGrowth factorBone morphogenic proteinBone morphogenic protein-2Molecular eventsMesenchymal stem cellsERK1/2 signalingProtein 2Morphogenic proteinStem cellsDifferentiationBMP2Critical roleTissue regenerationVivoSignalingCartilage repairProteinChondrogenesis
2009
ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor
Bai X, Wang D, Kong L, Zhang Y, Luan Y, Kobayashi T, Kronenberg H, Yu X, Liu C. ADAMTS-7, a Direct Target of PTHrP, Adversely Regulates Endochondral Bone Growth by Associating with and Inactivating GEP Growth Factor. Molecular And Cellular Biology 2009, 29: 4201-4219. PMID: 19487464, PMCID: PMC2715794, DOI: 10.1128/mcb.00056-09.Peer-Reviewed Original ResearchMeSH KeywordsADAM ProteinsADAMTS7 ProteinAnimalsBlotting, WesternBone and BonesBone DevelopmentCell DifferentiationCell LineCell Line, TumorChondrocytesGene Expression ProfilingHumansImmunohistochemistryImmunoprecipitationIntercellular Signaling Peptides and ProteinsMiceMice, KnockoutParathyroid Hormone-Related ProteinProgranulinsProtein BindingProtein PrecursorsReverse Transcriptase Polymerase Chain ReactionTissue Culture TechniquesTwo-Hybrid System TechniquesConceptsADAMTS-7Granulin-epithelin precursorEndochondral bone formationEndochondral bone growthGrowth factorBone formationChondrocyte differentiationBone growthDirect targetAutocrine growth factorGrowth plate chondrocytesProteolytic activityPTHrPChondrogenic growth factorsChondrocyte hypertrophyExtracellular matrix proteinsCartilage extracellular matrix proteinsImportant targetADAMTS familyInhibitionSkeletal developmentMatrix proteinsExpression patternsExtracellular matrixArthritis
2008
Regulation of chondrocyte differentiation by ADAMTS-12 metalloproteinase depends on its enzymatic activity
Bai X, Wang D, Luan Y, Yu X, Liu C. Regulation of chondrocyte differentiation by ADAMTS-12 metalloproteinase depends on its enzymatic activity. Cellular And Molecular Life Sciences 2008, 66: 667. PMID: 19151918, PMCID: PMC11131527, DOI: 10.1007/s00018-008-8633-x.Peer-Reviewed Original ResearchConceptsADAMTS-12Chondrocyte differentiationGrowth plate chondrocytesType X collagen expressionThrombospondin motifsPTHrPCollagen expressionAltered expressionMRNA levelsProminent expressionDownstream moleculesADAMTS familyMetalloproteinaseInhibitionEnzymatic activityNovel regulatorProteolytic activityChondrocytesExpressionChondrogenesisDifferentiationActivityMediation of Chondrogenic and Osteogenic Differentiation by an Interferon-Inducible p202 Protein
Kong L, Liu C. Mediation of Chondrogenic and Osteogenic Differentiation by an Interferon-Inducible p202 Protein. Cellular And Molecular Life Sciences 2008, 65: 3494-3506. PMID: 18791844, PMCID: PMC11131663, DOI: 10.1007/s00018-008-8342-5.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell LineChondrocytesChondrogenesisFeedback, PhysiologicalGene Expression Regulation, DevelopmentalGene Knockdown TechniquesGenes, ReporterGrowth PlateIntracellular Signaling Peptides and ProteinsMiceMice, Inbred C3HMice, KnockoutMice, TransgenicOsteoblastsOsteogenesisParathyroid Hormone-Related ProteinPluripotent Stem CellsRNA, Small InterferingSmad ProteinsConceptsParathyroid hormone-related peptideExpression of PTHrPHormone-related peptideCourse of osteogenesisGrowth plate chondrocytesInterferon-inducible proteinMolecular mechanism studiesInterferon-inducible p200 familyImportant mediatorP202 proteinOsteogenic differentiationSiRNA approachMouse embryosP202 expressionChondrocyte differentiationPositive feedback loopSmad transcription factorsTransgenic mouse embryosOsteoblast differentiationDifferential expressionExpressionC3H10T1/2 cellsC2C12 cellsDifferentiationCells