Featured Publications
Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis
Fu W, Vasylyev D, Bi Y, Zhang M, Sun G, Khleborodova A, Huang G, Zhao L, Zhou R, Li Y, Liu S, Cai X, He W, Cui M, Zhao X, Hettinghouse A, Good J, Kim E, Strauss E, Leucht P, Schwarzkopf R, Guo E, Samuels J, Hu W, Attur M, Waxman S, Liu C. Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis. Nature 2024, 625: 557-565. PMID: 38172636, PMCID: PMC10794151, DOI: 10.1038/s41586-023-06888-7.Peer-Reviewed Original ResearchVoltage-gated sodium channelsOA progressionDorsal root ganglion neuronsStructural joint damagePain relief treatmentHuman OA chondrocytesCommon joint diseaseMultiple mouse modelsNav1.7 blockersPain behaviorGanglion neuronsPharmacological blockadeJoint damageJoint degenerationChannel blockersJoint diseaseOA chondrocytesMouse modelTherapeutic targetOsteoarthritisIntracellular Ca2Nav1.7Nav1.7 channelsGenetic ablationLimited evidenceTNFR2/14-3-3ε 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 BOsteoarthritis
2024
Ion channels in osteoarthritis: emerging roles and potential targets
Zhou R, Fu W, Vasylyev D, Waxman S, Liu C. Ion channels in osteoarthritis: emerging roles and potential targets. Nature Reviews Rheumatology 2024, 20: 545-564. PMID: 39122910, DOI: 10.1038/s41584-024-01146-0.Peer-Reviewed Original ResearchIon channelsVoltage-dependent calcium channelsAcid-sensing ion channelsTransient receptor potential channelsVoltage-gated sodium channelsIon channel modulatorsFunction of ion channelsPotential clinical applicationsCalcium channelsPreclinical studiesClinical impactSymptomatic reliefPotassium channelsChloride channelsDisease-modifying treatmentsClinical trialsSodium channelsBone hyperplasiaChannel modulationIon channel biologySynovial inflammationClinical applicationPiezo channelsModel of OAPotential targetProgranulin deficiency associates with postmenopausal osteoporosis via increasing ubiquitination of estrogen receptor α
Li G, Wang A, Tang W, Fu W, Tian Q, Jian J, Lata M, Hettinghouse A, Ding Y, Wei J, Zhao X, Wang M, Dong Q, Liu C, Xu Y. Progranulin deficiency associates with postmenopausal osteoporosis via increasing ubiquitination of estrogen receptor α. Genes & Diseases 2024, 12: 101221. PMID: 39559258, PMCID: PMC11570241, DOI: 10.1016/j.gendis.2024.101221.Peer-Reviewed Original ResearchPostmenopausal osteoporosisEstrogen receptorReceptor AEstrogen signalingTreatment of postmenopausal osteoporosisOvariectomy-induced bone lossEstrogen-mediated inhibitionRegulation of bone mineral densityBone mineral densityEstrogen receptor aPGRN-deficient miceInhibition of osteoclastogenesisPostmenopausal womenEstrogen deficiencyMineral densityLoss of progranulinEstrogen regulationBone lossBone massPositive feedback regulatory loopBone resorptionOsteoporosisTherapeutic approachesEstrogenOsteoporosis model
2023
Unraveling the mechanisms behind joint damage
Fu W, Liu C. Unraveling the mechanisms behind joint damage. ELife 2023, 12: e89778. PMID: 37366155, PMCID: PMC10299819, DOI: 10.7554/elife.89778.Peer-Reviewed Original ResearchPathogenic mechanisms of glucocorticoid-induced osteoporosis
Chen M, Fu W, Xu H, Liu C. Pathogenic mechanisms of glucocorticoid-induced osteoporosis. Cytokine & Growth Factor Reviews 2023, 70: 54-66. PMID: 36906448, PMCID: PMC10518688, DOI: 10.1016/j.cytogfr.2023.03.002.Peer-Reviewed Original ResearchConceptsGlucocorticoid-induced osteoporosisExogenous glucocorticoidsGC excessBone cellsBone formationImpaired bone formationMultiple adverse effectsLong-term useExcessive glucocorticoidsAutoimmune diseasesBone resorptionPrescribed medicinesEnhanced osteoclastogenesisPathogenic mechanismsProcess of osteoblastogenesisGlucocorticoidsHigh dosesOsteoclast apoptosisApoptosis of osteoblastsMature osteoclastsAdverse effectsOsteoclastsDifferentiation of osteoblastsOsteoporosisOsteoclastogenesisTau deficiency inhibits classically activated macrophage polarization and protects against collagen-induced arthritis in mice
Chen M, Fu W, Xu H, Liu C. Tau deficiency inhibits classically activated macrophage polarization and protects against collagen-induced arthritis in mice. Arthritis Research & Therapy 2023, 25: 146. PMID: 37559125, PMCID: PMC10410869, DOI: 10.1186/s13075-023-03133-4.Peer-Reviewed Original ResearchConceptsInflammatory cell infiltrationPro-inflammatory cytokinesRheumatoid arthritisAnkle jointSerum levelsCell infiltrationMacrophage polarizationOsteoclast activityCartilage damagePathogenesis of RACollagen-induced arthritis modelTau-/- miceCollagen-induced arthritisInflammatory joint diseasePro-inflammatory functionsProgression of CIAPotential therapeutic targetRole of tauInflammatory arthritisBone erosionArthritis incidenceBone lossClinical scoresArthritis modelInflammatory disorders
2022
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 ResearchConceptsBlood-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 linePathologyPenfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases
Chen Y, Liu R, Cui Y, Hettinghouse A, Fu W, Zhang L, Zhang C, Liu C. Penfluridol targets acid sphingomyelinase to inhibit TNF signaling and is therapeutic against inflammatory autoimmune diseases. Arthritis Research & Therapy 2022, 24: 27. PMID: 35045889, PMCID: PMC8767691, DOI: 10.1186/s13075-021-02713-6.Peer-Reviewed Original ResearchConceptsInflammatory autoimmune diseaseAnti-TNF activityNF-κB activationInflammatory arthritisAutoimmune diseasesAcid sphingomyelinase activityTherapeutic effectTumor necrosis factor αInhibitory effectTNFα-transgenic miceCollagen-induced arthritisSeverity of arthritisInflammatory cytokine productionM1 macrophage polarizationBone marrow-derived macrophagesNecrosis factor αNF-κB activitySphingomyelinase activitySmall molecule drug libraryRAW 264.7 macrophage cell lineMarrow-derived macrophagesAcid sphingomyelinaseDrug affinity responsive target stabilityCytokine productionChronic schizophrenia
2021
Roles and Mechanisms of Irisin in Attenuating Pathological Features of Osteoarthritis
Li X, Zhu X, Wu H, Van Dyke T, Xu X, Morgan E, Fu W, Liu C, Tu Q, Huang D, Chen J. Roles and Mechanisms of Irisin in Attenuating Pathological Features of Osteoarthritis. Frontiers In Cell And Developmental Biology 2021, 9: 703670. PMID: 34650969, PMCID: PMC8509718, DOI: 10.3389/fcell.2021.703670.Peer-Reviewed Original ResearchMechanisms of irisinOA progressionKI miceKO miceOA mouse modelIntra-articular injectionNovel therapeutic targetPrimary chondrocytesPathological tissue samplesInflammatory factorsOA pathogenesisPathological featuresIntraarticular injectionInflammatory conditionsOA tissuesOsteoarthritis pathophysiologySevere OAIrisinJoint tissuesMouse modelCartilage degradationKnockout miceTherapeutic targetCartilage developmentTherapeutic potentialProgranulin 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 regulatorThe PGRN-TNFR2-14-3-3ε-ELK-1 axis regulates chondrocyte metabolism and osteoarthritis
Fu W, Chen M, Ding Y, Hettinghouse A, Liu C. The PGRN-TNFR2-14-3-3ε-ELK-1 axis regulates chondrocyte metabolism and osteoarthritis. Osteoarthritis And Cartilage 2021, 29: s191-s192. DOI: 10.1016/j.joca.2021.02.260.Peer-Reviewed Original Research
2020
Repurposing FDA-approved drugs for SARS-CoV-2 through an ELISA-based screening for the inhibition of RBD/ACE2 interaction
Fu W, Chen Y, Wang K, Hettinghouse A, Hu W, Wang J, Lei Z, Chen Z, Stapleford K, Liu C. Repurposing FDA-approved drugs for SARS-CoV-2 through an ELISA-based screening for the inhibition of RBD/ACE2 interaction. Protein & Cell 2020, 12: 586-591. PMID: 33210243, PMCID: PMC7673315, DOI: 10.1007/s13238-020-00803-w.Peer-Reviewed Original ResearchIn Vitro Physical and Functional Interaction Assays to Examine the Binding of Progranulin Derivative Atsttrin to TNFR2 and Its Anti-TNFα Activity
Fu W, Hettinghouse A, Liu C. In Vitro Physical and Functional Interaction Assays to Examine the Binding of Progranulin Derivative Atsttrin to TNFR2 and Its Anti-TNFα Activity. Methods In Molecular Biology 2020, 2248: 109-119. PMID: 33185871, PMCID: PMC8112733, DOI: 10.1007/978-1-0716-1130-2_8.Peer-Reviewed Original ResearchConceptsAnti-TNFα activityAutoimmune diseasesTartrate-resistant acid phosphatase (TRAP) stainingAnti-TNFα therapyCollagen-induced arthritisInflammatory disease modelsGood therapeutic effectAcid phosphatase stainingGrowth factor-like moleculesTNF inhibitorsTherapeutic effectTNFα activityProgranulinFunctional inhibitionTNFR2AtsttrinDisease modelsPhosphatase stainingTNFRTNFαDiseaseInhibitionCritical roleDirect bindingHigh affinityMonitoring Atsttrin-Mediated Inhibition of TNFα/NF-κβ Activation Through In Vivo Bioluminescence Imaging
Hettinghouse A, Fu W, Liu C. Monitoring Atsttrin-Mediated Inhibition of TNFα/NF-κβ Activation Through In Vivo Bioluminescence Imaging. Methods In Molecular Biology 2020, 2248: 201-210. PMID: 33185877, PMCID: PMC8140391, DOI: 10.1007/978-1-0716-1130-2_14.Peer-Reviewed Original ResearchConceptsTumor necrosis factorDouble mutant miceNF-κBOverexpression of TNFMutant miceBioluminescence imagingTransgenic reporter mouse modelNF-κB luciferaseNF-κβ activationVivo bioluminescence imagingReporter mouse modelAutoimmune conditionsTNF-TgNF-κβNecrosis factorImmune responseMouse modelMolecular mediatorsTransgenic modelTherapeutic objectivesVivo efficacyProgranulinPotential therapeuticsAtsttrinLuciferase activity
2019
Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis
Liu R, Chen Y, Fu W, Wang S, Cui Y, Zhao X, Lei Z, Hettinghouse A, Liu J, Wang C, Zhang C, Bi Y, Xiao G, Chen Z, Liu C. Fexofenadine inhibits TNF signaling through targeting to cytosolic phospholipase A2 and is therapeutic against inflammatory arthritis. Annals Of The Rheumatic Diseases 2019, 78: 1524. PMID: 31302596, PMCID: PMC8157820, DOI: 10.1136/annrheumdis-2019-215543.Peer-Reviewed Original ResearchConceptsAnti-TNF activityCytosolic phospholipase A2Inflammatory arthritisTNF-α transgenic miceInflammatory arthritis modelInflammatory rheumatic diseasesCollagen-induced arthritisAnti-inflammatory activityPhospholipase A2New therapeutic interventionsActivated B cellsTNF-α signalingNecrosis factor-alpha signalingDrug affinity responsive target stabilityDBA/1 miceRheumatic diseasesArthritis modelAutoimmune diseasesCellular thermal shiftSerial screeningB cellsTransgenic miceArthritisDrug AdministrationTherapeutic interventions
2018
Role 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 regulatorTHU0056 14–3–3 is a molecular switch regulating macrophage polarisation in inflammatory arthritis
Fu W, Hettinghouse A, Liu C. THU0056 14–3–3 is a molecular switch regulating macrophage polarisation in inflammatory arthritis. Annals Of The Rheumatic Diseases 2018, 77: 252. DOI: 10.1136/annrheumdis-2018-eular.4729.Peer-Reviewed Original ResearchAnti-inflammatory actionTNF receptor 2Mean fluorescence intensityAnti-inflammation actionClinical arthritis scoreInflammatory arthritisCIA miceAnti-inflammatory effectsAnti-inflammatory activityMacrophage polarizationProtective effectArthritis scoreCritical downstream mediatorM2 polarizationΔ miceM1-M2 polarizationPresence of progranulinAnti-inflammatory pathwaySeverity of CIADownstream mediatorSignificant decreasePercentage of CD206Hallmarks of macrophagesPGRN effectsWT miceOP0224 Adamts-12 protects against inflammatory arthritis through interacting with proinflammatory ctgf
Fu W, Wei J, Hettinghouse A, He W, Liu C. OP0224 Adamts-12 protects against inflammatory arthritis through interacting with proinflammatory ctgf. Annals Of The Rheumatic Diseases 2018, 77: 160. DOI: 10.1136/annrheumdis-2018-eular.4748.Peer-Reviewed Original ResearchCollagen-induced arthritisClinical arthritis scoreInflammatory arthritisADAMTS-12Arthritis scoreCTGF antibodyIL-1βDisease onsetHistological analysisAccelerated disease onsetCIA mouse modelAnti-inflammatory cytokinesRheumatoid arthritis developmentPro-inflammatory roleFurther tissue destructionDestruction of boneSignificant increaseCritical regulatorCIA miceRA patientsArthritis developmentArthritis incidenceKO miceNormal inflammationSafranin O staining