2021
An Unanticipated Role for Sphingosine Kinase-2 in Bone and in the Anabolic Effect of Parathyroid Hormone
Walker JM, Yao GQ, Siu E, Zhu M, Sun BH, Simpson C, Insogna KL. An Unanticipated Role for Sphingosine Kinase-2 in Bone and in the Anabolic Effect of Parathyroid Hormone. Endocrinology 2021, 162: bqab042. PMID: 33640975, PMCID: PMC8095390, DOI: 10.1210/endocr/bqab042.Peer-Reviewed Original ResearchConceptsSphk2-/- miceParathyroid hormoneAnabolic responseFemoral trabecular BV/TVLower spinal bone mineral densityTrabecular BV/TVSpinal bone mineral densityDaily parathyroid hormoneFemoral bone volumeSuppression of sclerostinEnd of treatmentNormal bone massBone mineral densityNormal bone remodelingRole of SphK1BV/TVFemale control animalsSphingosine kinase 2Sphingosine kinaseControl miceLow BMDAnabolic effectsBone massMineral densityControl animalsSelective deletion of the receptor for CSF1, c-fms, in osteoclasts results in a high bone mass phenotype, smaller osteoclasts in vivo and an impaired response to an anabolic PTH regimen
Zhu M, Sun BH, Nevius E, Kaplan J, Pereira J, Insogna K. Selective deletion of the receptor for CSF1, c-fms, in osteoclasts results in a high bone mass phenotype, smaller osteoclasts in vivo and an impaired response to an anabolic PTH regimen. PLOS ONE 2021, 16: e0247199. PMID: 33607650, PMCID: PMC7895546, DOI: 10.1371/journal.pone.0247199.Peer-Reviewed Original ResearchConceptsColony stimulating factor 1Mature osteoclastsBone massHigh bone mass phenotypeAttenuated anabolic responseDaily subcutaneous dosesTrabecular bone massBone mass phenotypeC-fmsNormal tooth eruptionTrabecular bone compartmentsMature osteoclast functionCathepsin K promoterFemurs of maleWild-type animalsOcS/BSFemale knockSubcutaneous dosesNormal weightSmall osteoclastsImpaired responseTrabecular numberAnabolic responseFlox miceMass phenotype
2018
The contribution of cross-talk between the cell-surface proteins CD36 and CD47–TSP-1 in osteoclast formation and function
Koduru SV, Sun BH, Walker JM, Zhu M, Simpson C, Dhodapkar M, Insogna KL. The contribution of cross-talk between the cell-surface proteins CD36 and CD47–TSP-1 in osteoclast formation and function. Journal Of Biological Chemistry 2018, 293: 15055-15069. PMID: 30082316, PMCID: PMC6166722, DOI: 10.1074/jbc.ra117.000633.Peer-Reviewed Original ResearchConceptsOsteoclast formationTSP-1Competitive NO synthase inhibitorPro-osteoclastogenic effectAntibody-mediated blockadeNitroarginine methyl esterNO synthase inhibitorNitric Oxide SignalingPTH infusionDifferentiation 47Parathyroid hormoneBone resorptionFemale miceHypercalcemic responseOsteoclast maturationSynthase inhibitorResorptive activitySynthetic agonistsCD36Osteoclast progenitorsMiceInhibitory effectCD47OsteoclastsWT osteoblasts
2017
Breast cancer-associated gene 3 interacts with Rac1 and augments NF-κB signaling in vitro, but has no effect on RANKL-induced bone resorption in vivo
Yao C, Yu KP, Philbrick W, Sun BH, Simpson C, Zhang C, Insogna K. Breast cancer-associated gene 3 interacts with Rac1 and augments NF-κB signaling in vitro, but has no effect on RANKL-induced bone resorption in vivo. International Journal Of Molecular Medicine 2017, 40: 1067-1077. PMID: 28791343, PMCID: PMC5593463, DOI: 10.3892/ijmm.2017.3091.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsBone ResorptionCathepsin KCell LineFemaleFemurFibroblastsGene Expression RegulationHEK293 CellsHeLa CellsHumansMaleMiceMice, Inbred C57BLMice, TransgenicNeuropeptidesNF-kappa BOrgan SpecificityOsteoclastsPromoter Regions, GeneticRac1 GTP-Binding ProteinRANK LigandSignal TransductionTibiaConceptsNF-κB signalingCell type-dependent roleCritical downstream targetNF-κBCanonical NF-κB signalingNuclear factorReceptor activatorNuclear Rac1Adaptor proteinCancer-associated genesMature osteoclast formationSmall GTPaseDownstream targetsExogenous receptor activatorLow-dose RANKLNF-κB interactionTransgenic animalsImportant regulatorBreast cancer-associated genesWild-type littermatesCell typesRac1SignalingBCA3Dependent role
2016
The liver throws the skeleton a bone (resorption factor)
Chung C, Insogna KL. The liver throws the skeleton a bone (resorption factor). Hepatology 2016, 64: 977-979. PMID: 27312397, PMCID: PMC4992574, DOI: 10.1002/hep.28688.Peer-Reviewed Original Research
2015
Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age‐Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo
Zhu M, Sun B, Saar K, Simpson C, Troiano N, Dallas SL, Tiede‐Lewis L, Nevius E, Pereira JP, Weinstein RS, Tommasini SM, Insogna KL. Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age‐Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. Journal Of Bone And Mineral Research 2015, 31: 864-873. PMID: 26496249, PMCID: PMC4826801, DOI: 10.1002/jbmr.2733.Peer-Reviewed Original ResearchConceptsDual-energy X-ray absorptiometryBone mineral densityDKO miceParathyroid hormoneOsteoclast numberDKO animalsSerum cross-linked C-telopeptideCross-linked C-telopeptideDaily parathyroid hormoneTrabecular bone massX-ray absorptiometryMetaphyseal trabecular boneNormal differentiation markersAge-dependent changesC-telopeptideMineral densityBone massBone densityActin ring formationSkeletal metabolismOsteoblast numberTooth eruptionResorptive activityNormal responseFocal disruption
2014
The Transcription Factor T-box 3 Regulates Colony-stimulating Factor 1-dependent Jun Dimerization Protein 2 Expression and Plays an Important Role in Osteoclastogenesis*
Yao C, Yao GQ, Sun BH, Zhang C, Tommasini SM, Insogna K. The Transcription Factor T-box 3 Regulates Colony-stimulating Factor 1-dependent Jun Dimerization Protein 2 Expression and Plays an Important Role in Osteoclastogenesis*. Journal Of Biological Chemistry 2014, 289: 6775-6790. PMID: 24394418, PMCID: PMC3945339, DOI: 10.1074/jbc.m113.499210.Peer-Reviewed Original Research
2012
LIM kinase 1 deficient mice have reduced bone mass
Kawano T, Zhu M, Troiano N, Horowitz M, Bian J, Gundberg C, Kolodziejczak K, Insogna K. LIM kinase 1 deficient mice have reduced bone mass. Bone 2012, 52: 70-82. PMID: 23017662, PMCID: PMC3688839, DOI: 10.1016/j.bone.2012.09.024.Peer-Reviewed Original ResearchConceptsLIM kinase 1Cytoskeletal remodelingRole of LIMK1Specialized cellular functionsActin cytoskeletal remodelingActin-severing proteinBone cell biologyNormal osteoblast differentiationCellular functionsCell biologyCell motilityCell shapeKinase 1Cell cycleF-actinOsteoblast differentiationPhospho-cofilinActin monomersSkeletal phenotypeOsteoblast coloniesOsteoblastsMetalloproteinase activityDifferentiationRemodelingRate of mineralization
2011
Selective deletion of the membrane-bound colony stimulating factor 1 isoform leads to high bone mass but does not protect against estrogen-deficiency bone loss
Yao GQ, Wu JJ, Troiano N, Zhu ML, Xiao XY, Insogna K. Selective deletion of the membrane-bound colony stimulating factor 1 isoform leads to high bone mass but does not protect against estrogen-deficiency bone loss. Journal Of Bone And Mineral Metabolism 2011, 30: 408-418. PMID: 22105655, PMCID: PMC4378684, DOI: 10.1007/s00774-011-0336-y.Peer-Reviewed Original ResearchAnimalsBone and BonesBone DensityCell DifferentiationCells, CulturedCoculture TechniquesColony-Stimulating FactorsFemaleHumansHypertriglyceridemiaMaleMiceMice, KnockoutOsteoblastsOsteoclastsOsteoporosisOsteoporosis, PostmenopausalProtein IsoformsRNA, MessengerSex CharacteristicsSolubilityUp-Regulation
2010
Osteoclasts Lacking Rac2 Have Defective Chemotaxis and Resorptive Activity
Itokowa T, Zhu ML, Troiano N, Bian J, Kawano T, Insogna K. Osteoclasts Lacking Rac2 Have Defective Chemotaxis and Resorptive Activity. Calcified Tissue International 2010, 88: 75-86. PMID: 21110188, PMCID: PMC3155765, DOI: 10.1007/s00223-010-9435-3.Peer-Reviewed Original ResearchConceptsTrabecular bone massBone massMature osteoclastsFemoral cortical thicknessTotal bone areaNumber of osteoclastsWild-type miceNormal tooth eruptionNumber of osteoblastsWild-type animalsBone resorptionCortical porosityActin ring formationCortical thicknessTooth eruptionOsteoclast functionResorptive activityDefective chemotaxisBone areaFemale animalsMiceOsteoclastsMigratory rateNormal sizeSignificant differencesTargeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH treatment in mice
Yao GQ, Wu JJ, Troiano N, Insogna K. Targeted overexpression of Dkk1 in osteoblasts reduces bone mass but does not impair the anabolic response to intermittent PTH treatment in mice. Journal Of Bone And Mineral Metabolism 2010, 29: 141-148. PMID: 20602130, PMCID: PMC3457021, DOI: 10.1007/s00774-010-0202-3.Peer-Reviewed Original ResearchConceptsParathyroid hormonePTH treatmentBone massTg miceAnabolic responseDKK1 expressionSingle daily subcutaneous doseDaily subcutaneous doseBone formationIntermittent PTH treatmentPotent anabolic agentOverexpression of DKK1Number of osteoblastsSubcutaneous doseWT miceReal-time PCRSkeletal sitesDickkopf-1Anabolic agentsBody weightTransgenic miceHistomorphometric parametersHistomorphometric analysisTargeted overexpressionPrimary murine osteoblasts
2009
Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease
Kukreja A, Radfar S, Sun BH, Insogna K, Dhodapkar MV. Dominant role of CD47–thrombospondin-1 interactions in myeloma-induced fusion of human dendritic cells: implications for bone disease. Blood 2009, 114: 3413-3421. PMID: 19661269, PMCID: PMC2765677, DOI: 10.1182/blood-2009-03-211920.Peer-Reviewed Original ResearchConceptsHuman dendritic cellsDendritic cellsBone diseaseOsteoclast formationRecruitment of DCsTumor cellsThrombospondin-1Regulation of CD47Tumor-associated osteoclastsNuclear factor-kappaB ligandMyeloma bone diseaseLytic bone diseasePrimary myeloma cellsHuman osteoclast formationMyeloma cell linesParathyroid hormoneKappaB ligandReceptor activatorOsteoclast precursorsGiant cellsSpontaneous cell-cell fusionMyeloma cellsHuman monocytesMyeloma tumorsDisease
2008
The Anabolic Response to Parathyroid Hormone Is Augmented in Rac2 Knockout Mice
Kawano T, Troiano N, Adams DJ, Wu JJ, Sun BH, Insogna K. The Anabolic Response to Parathyroid Hormone Is Augmented in Rac2 Knockout Mice. Endocrinology 2008, 149: 4009-4015. PMID: 18467443, PMCID: PMC2488220, DOI: 10.1210/en.2008-0034.Peer-Reviewed Original ResearchConceptsAnabolic responseType 1 collagenWild-type animalsPTH treatmentKnockout miceResorptive activityAvailable anabolic therapyTotal bone densityAge-matched wild-type animalsSerum aminoterminal propeptideWild-type groupRac2 knockout miceGroups of animalsAnabolic therapyParathyroid hormoneResorptive responseSerum markersOsteoclast numberTherapeutic responseAminoterminal propeptideBone massBone densitySkeletal responseCortical thicknessGenetic absenceExpression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling
Garimella R, Tague SE, Zhang J, Belibi F, Nahar N, Sun BH, Insogna K, Wang J, Anderson HC. Expression and Synthesis of Bone Morphogenetic Proteins by Osteoclasts: A Possible Path to Anabolic Bone Remodeling. Journal Of Histochemistry & Cytochemistry 2008, 56: 569-577. PMID: 18319273, PMCID: PMC2386763, DOI: 10.1369/jhc.2008.950394.Peer-Reviewed Original ResearchMeSH KeywordsAcid PhosphataseAnimalsBlotting, WesternBone Marrow CellsBone Morphogenetic ProteinsBone RemodelingCoculture TechniquesFemurImmunohistochemistryIn Situ HybridizationIsoenzymesMiceOsteoclastsReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSkullTartrate-Resistant Acid PhosphataseTibiaConceptsBone morphogenetic proteinBMP-2Morphogenetic proteinsBMP-6 mRNAExpression of transcriptsMouse calvarial osteoblastsDifferentiation of osteoblastsBMP-4Osteoclast lysatesOrchestrated processIntercellular communicationReal-time PCRCalvarial osteoblastsBone marrow cellsSitu hybridizationDirect rolePossible direct roleProteinWestern blottingBone remodeling siteBone formationOsteoblastsAnabolic boneMarrow cellsExpression
2007
Breast Cancer–Associated Gene 3 (BCA3) Is a Novel Rac1‐Interacting Protein*
Yu K, Itokawa T, Zhu M, Syam S, Seth A, Insogna K. Breast Cancer–Associated Gene 3 (BCA3) Is a Novel Rac1‐Interacting Protein*. Journal Of Bone And Mineral Research 2007, 22: 628-637. PMID: 17227220, DOI: 10.1359/jbmr.070105.Peer-Reviewed Original Research
2006
Colony-Stimulating Factor-1 Increases Osteoclast Intracellular pH and Promotes Survival via the Electroneutral Na/HCO3 Cotransporter NBCn1
Bouyer P, Sakai H, Itokawa T, Kawano T, Fulton CM, Boron WF, Insogna KL. Colony-Stimulating Factor-1 Increases Osteoclast Intracellular pH and Promotes Survival via the Electroneutral Na/HCO3 Cotransporter NBCn1. Endocrinology 2006, 148: 831-840. PMID: 17068143, DOI: 10.1210/en.2006-0547.Peer-Reviewed Original ResearchMeSH Keywords4,4'-Diisothiocyanostilbene-2,2'-Disulfonic AcidAlkaliesAmilorideAnimalsBicarbonatesCarbon DioxideCaspase InhibitorsCell SeparationCell SurvivalCells, CulturedEnzyme InhibitorsHydrogen-Ion ConcentrationIntracellular FluidMacrolidesMacrophage Colony-Stimulating FactorMiceMice, Inbred StrainsOsteoclastsProtonsRatsSodiumSodium-Bicarbonate SymportersConceptsProlong osteoclast survivalOsteoclast-like cellsColony-stimulating factor-1Osteoclast survivalCotransporter NBCn1Survival of osteoclastsHCO3- cotransporter NBCn1Caspase-8Inhibition of apoptosisExtracellular sodiumPromotes SurvivalOsteoclastsRT-PCRCellular alkalinizationSurvivalFactor 1Caspase-3NBCn1Intracellular pHCell survivalElectroneutral Na/Block activationPresent studySame extentFirst evidenceEffects of glucose-dependent insulinotropic peptide on osteoclast function
Zhong Q, Itokawa T, Sridhar S, Ding KH, Xie D, Kang B, Bollag WB, Bollag RJ, Hamrick M, Insogna K, Isales CM. Effects of glucose-dependent insulinotropic peptide on osteoclast function. AJP Endocrinology And Metabolism 2006, 292: e543-e548. PMID: 17003233, DOI: 10.1152/ajpendo.00364.2006.Peer-Reviewed Original ResearchConceptsGlucose-dependent insulinotropic peptideBone resorptionNutrient ingestionGIP receptorOrgan culture systemBone breakdownEffects of GIPOsteoclast functionMature osteoclastsGlucose-induced insulin secretionGIP receptor transcriptsImmediate postprandial periodBone formationAnti-resorptive effectsGlucose-dependent insulinotropicIntestinal endocrine cellsOsteoclast resorptive activityPostprandial reductionIncretin hormonesInsulinotropic peptidePostprandial periodInsulin secretionResorptive activityOsteoclastic cellsReceptor transcriptsActivated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts
Sakai H, Chen Y, Itokawa T, Yu KP, Zhu ML, Insogna K. Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Bone 2006, 39: 1290-1301. PMID: 16950670, DOI: 10.1016/j.bone.2006.06.012.Peer-Reviewed Original ResearchMeSH KeywordsActinsAndrostadienesAnimalsBiological Transport, ActiveCdc42 GTP-Binding ProteinCells, CulturedCytoskeletonEnzyme InhibitorsGuanosine TriphosphateHumansMacrophage Colony-Stimulating FactorMiceModels, BiologicalOsteoclastsPhosphoinositide-3 Kinase InhibitorsProtein BindingProto-Oncogene Proteins c-vavPseudopodiaRac GTP-Binding ProteinsRatsReceptor, Macrophage Colony-Stimulating FactorRecombinant ProteinsSignal TransductionWortmanninConceptsCSF-1GEF activityCytoskeletal remodelingGTPase activityAssociation of VavC-fmsRac GTPase activityDominant negative Cdc42Dominant-negative RacCSF-1 receptorInhibitors of PI3CSF-1 treatmentTarget GTPaseActive RacExchange factorActive Cdc42Actin reorganizationLamellipodia formationPhosphotyrosine contentC-SrcPlasma membraneInhibitor of RhoARapid translocationVavRac translocation
2005
CSF-1 Induces fos Gene Transcription and Activates the Transcription Factor Elk-1 in Mature Osteoclasts
Yao G, Itokawa T, Paliwal I, Insogna K. CSF-1 Induces fos Gene Transcription and Activates the Transcription Factor Elk-1 in Mature Osteoclasts. Calcified Tissue International 2005, 76: 371-378. PMID: 15812575, DOI: 10.1007/s00223-004-0099-8.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornCell NucleusCells, CulturedDNA-Binding ProteinsEts-Domain Protein Elk-1Genes, fosMacrophage Colony-Stimulating FactorMiceMice, TransgenicOsteoclastsProto-Oncogene ProteinsProto-Oncogene Proteins c-fosRNA, MessengerTranscription FactorsTranscription, GeneticTranscriptional ActivationConceptsTranscription factor Elk-1Serum response elementTranscriptional activationElk-1CSF-1Response elementMature osteoclastsNuclear c-Fos proteinRegulation of FosBacterial lac Z geneC-fosSap-1aFos serum response elementFos promoterNuclear proteinsGene transcriptionFos geneMolecular mechanismsLac Z geneVehicle-treated cellsTargeted deletionFactor 1Absolute requirementC-Fos proteinLike cells
2003
The Cell Surface Form of Colony-Stimulating Factor-1 Is Biologically Active in Bone in Vivo
Yao GQ, Wu JJ, Sun BH, Troiano N, Mitnick MA, Insogna K. The Cell Surface Form of Colony-Stimulating Factor-1 Is Biologically Active in Bone in Vivo. Endocrinology 2003, 144: 3677-3682. PMID: 12865350, DOI: 10.1210/en.2002-221071.Peer-Reviewed Original ResearchConceptsOp/op miceWild-type miceOp miceBone densityTooth eruptionTransgenic micePeripheral quantitative computed tomographyMCSF-1Factor 1Number of osteoclastsQuantitative computed tomographyOp/op animalsMolar tooth eruptionWild-type animalsOP animalsComputed tomographyColony-stimulating factor-1Colony stimulating factor 1Normal incisorsHistomorphometric analysis