Featured Publications
Catalysis‐Independent ENPP1 Protein Signaling Regulates Mammalian Bone Mass
Zimmerman K, Liu X, von Kroge S, Stabach P, Lester ER, Chu EY, Srivastava S, Somerman MJ, Tommasini SM, Busse B, Schinke T, Carpenter TO, Oheim R, Braddock DT. Catalysis‐Independent ENPP1 Protein Signaling Regulates Mammalian Bone Mass. Journal Of Bone And Mineral Research 2020, 37: 1733-1749. PMID: 35773783, PMCID: PMC9709593, DOI: 10.1002/jbmr.4640.Peer-Reviewed Original ResearchConceptsHeterotopic mineralizationBone massFibroblast growth factor 23Growth factor 23Low bone massSoft tissue calcificationEarly-onset osteoporosisFrizzled-related protein 1Soluble Wnt inhibitorsTrabecular bone microarchitectureENPP1 deficiencyΒ-catenin signalingFactor 23Plasma FGF23Vascular calcificationArterial calcificationNuclear β-cateninPlasma PPiBone microarchitectureMurine modelTissue calcificationPlasma PiWnt inhibitorsCalcificationMiceIdentification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early‐Onset Osteoporosis
Kato H, Ansh AJ, Lester ER, Kinoshita Y, Hidaka N, Hoshino Y, Koga M, Taniguchi Y, Uchida T, Yamaguchi H, Niida Y, Nakazato M, Nangaku M, Makita N, Takamura T, Saito T, Braddock DT, Ito N. Identification of ENPP1 Haploinsufficiency in Patients With Diffuse Idiopathic Skeletal Hyperostosis and Early‐Onset Osteoporosis. Journal Of Bone And Mineral Research 2020, 37: 1125-1135. PMID: 35340077, PMCID: PMC9177665, DOI: 10.1002/jbmr.4550.Peer-Reviewed Original ResearchConceptsAutosomal recessive hypophosphatemic rickets type 2Diffuse idiopathic skeletal hyperostosisEarly-onset osteoporosisENPP1 variantsHypophosphatemic ricketsENPP1 mutationsFibroblast growth factor 23Case 1Growth factor 23Serum phosphate levelsIdiopathic skeletal hyperostosisPosterior longitudinal ligamentCase 3Spinal ligament ossificationFactor 23Skeletal hyperostosisArterial calcificationLongitudinal ligamentPresumptive diagnosisLigament ossificationSevere ossificationMutational statusType 2Pathogenic lossGenetic testing
2022
The cardiomyocyte disrupts pyrimidine biosynthesis in non-myocytes to regulate heart repair
Li S, Yokota T, Wang P, Hoeve J, Ma F, Le TM, Abt ER, Zhou Y, Wu R, Nanthavongdouangsy M, Rodriguez A, Wang Y, Lin YJ, Muranaka H, Sharpley M, Braddock DT, MacRae VE, Banerjee U, Chiou PY, Seldin M, Huang D, Teitell M, Gertsman I, Jung M, Bensinger SJ, Damoiseaux R, Faull K, Pellegrini M, Lusis A, Graeber TG, Radu CG, Deb A. The cardiomyocyte disrupts pyrimidine biosynthesis in non-myocytes to regulate heart repair. Journal Of Clinical Investigation 2022, 132: e149711. PMID: 34813507, PMCID: PMC8759793, DOI: 10.1172/jci149711.Peer-Reviewed Original ResearchConceptsCardiac injuryHeart repairENPP1 inhibitorsPyrimidine biosynthesisHeart injuryIschemic cardiac injuryAdministration of uridineEctonucleotide pyrophosphatase/phosphodiesterase 1Augmenting tissue repairP53-mediated cell deathSmall molecule screeningCardiac muscle cellsPyrophosphatase/phosphodiesterase 1Systemic administrationNonmyocyte cellsMurine modelHeart functionCardiac repairGenotoxic stressInjuryIntercellular regulationMuscle cellsPopulation of cellsExtracellular ATPMolecule screening
2020
Response of the ENPP1‐Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice
Ferreira CR, Kavanagh D, Oheim R, Zimmerman K, Stürznickel J, Li X, Stabach P, Rettig RL, Calderone L, MacKichan C, Wang A, Hutchinson HA, Nelson T, Tommasini SM, von Kroge S, Fiedler IA, Lester ER, Moeckel GW, Busse B, Schinke T, Carpenter TO, Levine MA, Horowitz MC, Braddock DT. Response of the ENPP1‐Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice. Journal Of Bone And Mineral Research 2020, 36: 942-955. PMID: 33465815, PMCID: PMC8739051, DOI: 10.1002/jbmr.4254.Peer-Reviewed Original ResearchConceptsBone mineral densityLow bone mineral densityTrabecular bone massBone massEarly-onset osteoporosisAsj/Conventional therapyLower trabecular bone massGreater bone fragilityRisk of nephrocalcinosisHigh-phosphate dietLow bone massCortical bone massDevelopment of nephrocalcinosisBone biomechanical propertiesAcademic medical centerPlasma phosphorus concentrationsAutosomal recessive hypophosphatemic ricketsRecessive hypophosphatemic ricketsENPP1 deficiencyRachitic phenotypeMedullary nephrocalcinosisRenal failureNormal chowMineral densityMusculoskeletal Comorbidities and Quality of Life in ENPP1‐Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models
Ferreira CR, Ansh AJ, Nester C, O'Brien C, Stabach PR, Murtada S, Lester ER, Khursigara G, Molloy L, Carpenter TO, Braddock DT. Musculoskeletal Comorbidities and Quality of Life in ENPP1‐Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models. Journal Of Bone And Mineral Research 2020, 37: 494-504. PMID: 34882836, PMCID: PMC9667476, DOI: 10.1002/jbmr.4487.Peer-Reviewed Original ResearchConceptsENPP1 deficiencyAsj/Musculoskeletal complicationsBrief Pain Inventory-Short FormPhysical Function Short FormFibroblast growth factor 23Achilles tendon calcificationHealth-related qualityMajority of patientsGrowth factor 23Cervical spine fusionPresence of enthesopathyQuality of lifeAnalgesic medicationRegular chowResidual painAdult patientsDose escalationFactor 23Replacement therapyPhysical functionCardiovascular calcificationTendon calcificationAchilles tendonSpine fusionImproving the Pharmacodynamics and In Vivo Activity of ENPP1‐Fc Through Protein and Glycosylation Engineering
Stabach PR, Zimmerman K, Adame A, Kavanagh D, Saeui CT, Agatemor C, Gray S, Cao W, De La Cruz EM, Yarema KJ, Braddock DT. Improving the Pharmacodynamics and In Vivo Activity of ENPP1‐Fc Through Protein and Glycosylation Engineering. Clinical And Translational Science 2020, 14: 362-372. PMID: 33064927, PMCID: PMC7877847, DOI: 10.1111/cts.12887.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsArea Under CurveDisease Models, AnimalEnzyme Replacement TherapyGlycosylationHalf-LifeHistocompatibility Antigens Class IHumansMaleMice, TransgenicPhosphoric Diester HydrolasesProtein EngineeringProtein Structure, TertiaryPyrophosphatasesReceptors, FcRecombinant Fusion ProteinsVascular CalcificationConceptsProtein engineeringO-BuN-glycansGlycosylation engineeringCellular recyclingENPP1-deficient miceTerminal sialylationBiomanufacturing platformProtein therapeuticsCalcification disordersSialylationCellsVivo activityFc neonatal receptorTherapeuticsArterial calcificationProteinMurine modelManNAcEnzyme replacementNeonatal receptorEfficacious levelsGeneral strategyThree-prong strategyDrug potencyGenetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization
Maulding ND, Kavanagh D, Zimmerman K, Coppola G, Carpenter TO, Jue NK, Braddock DT. Genetic pathways disrupted by ENPP1 deficiency provide insight into mechanisms of osteoporosis, osteomalacia, and paradoxical mineralization. Bone 2020, 142: 115656. PMID: 32980560, PMCID: PMC7744330, DOI: 10.1016/j.bone.2020.115656.Peer-Reviewed Original ResearchConceptsGenetic pathwaysSkeletal phenotypeGene expressionHuman disease phenotypesAsj/Suppression of WntTranscript countsGene transcriptionENPP1-deficient miceGene pathwaysEnzyme functionENPP1 deficiencyWnt ligandsSoluble Wnt inhibitorsWnt activityReduced gene transcriptionBiomechanical phenotypeTranscriptionWnt inhibitorsBone findingsUnbiased analysisDisease phenotypePhenotypeOld miceStrong signature
2019
Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations
Kotwal A, Ferrer A, Kumar R, Singh RJ, Murthy V, Schultz-Rogers L, Zimmermann M, Lanpher B, Zimmerman K, Stabach PR, Klee E, Braddock DT, Wermers RA. Clinical and Biochemical Phenotypes in a Family With ENPP1 Mutations. Journal Of Bone And Mineral Research 2019, 35: 662-670. PMID: 31826312, PMCID: PMC7771569, DOI: 10.1002/jbmr.3938.Peer-Reviewed Original ResearchConceptsAutosomal recessive hypophosphatemic rickets type 2Biallelic mutationsMonoallelic mutationsPrimary hyperparathyroidismPathogenic variantsCarotid intima-media thicknessClassic disease manifestationsNormocalcemic primary hyperparathyroidismC-terminal FGF23Intima-media thicknessWhole-exome sequencingClinical findingsArterial calcificationPeriarticular calcificationSpectrum of phenotypesIntact FGF23Disease manifestationsBilateral femursENPP1 variantsBone deformitiesBiochemical manifestationsType 2ENPP1 geneExome sequencingHyperparathyroidismHuman Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency
Oheim R, Zimmerman K, Maulding ND, Stürznickel J, von Kroge S, Kavanagh D, Stabach PR, Kornak U, Tommasini SM, Horowitz MC, Amling M, Thompson D, Schinke T, Busse B, Carpenter TO, Braddock DT. Human Heterozygous ENPP1 Deficiency Is Associated With Early Onset Osteoporosis, a Phenotype Recapitulated in a Mouse Model of Enpp1 Deficiency. Journal Of Bone And Mineral Research 2019, 35: 528-539. PMID: 31805212, PMCID: PMC7184798, DOI: 10.1002/jbmr.3911.Peer-Reviewed Original ResearchConceptsAutosomal recessive hypophosphatemic rickets type 2ENPP1 deficiencyEarly-onset osteoporosisGene-dose effectOnset osteoporosisAsj/Bone mineral density scansBone mineralization disturbancesRenal phosphate wastingCortical boneDose effectMild osteomalaciaMineralization disturbancesFGF23 levelsMild elevationPlasma FGF23Arterial calcificationBone massPhosphate wastingSkeletal manifestationsBone fragilityThoracic spineWild-type family membersType 2Adult men
2017
Intraperitoneal pyrophosphate treatment reduces renal calcifications in Npt2a null mice
Caballero D, Li Y, Fetene J, Ponsetto J, Chen A, Zhu C, Braddock DT, Bergwitz C. Intraperitoneal pyrophosphate treatment reduces renal calcifications in Npt2a null mice. PLOS ONE 2017, 12: e0180098. PMID: 28704395, PMCID: PMC5509111, DOI: 10.1371/journal.pone.0180098.Peer-Reviewed Original ResearchConceptsRenal calcificationCompared to WT miceElevated urinary excretionRenal stone diseaseNucleotide pyrophosphatase phosphodiesterase 1WT miceDietary calciumUrinary excretionIntraperitoneal administrationStone diseaseNull miceMouse mutationMiceCalcificationNephrocalcinosisNpt2aDisordersUnrecognized factorsContribution of genotypePresent studyPhosphodiesterase 1PPINpt2cPatientsNephrolithiasis
2015
ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy
Albright RA, Stabach P, Cao W, Kavanagh D, Mullen I, Braddock AA, Covo MS, Tehan M, Yang G, Cheng Z, Bouchard K, Yu ZX, Thorn S, Wang X, Folta-Stogniew EJ, Negrete A, Sinusas AJ, Shiloach J, Zubal G, Madri JA, De La Cruz EM, Braddock DT. ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy. Nature Communications 2015, 6: 10006. PMID: 26624227, PMCID: PMC4686714, DOI: 10.1038/ncomms10006.Peer-Reviewed Original ResearchConceptsChronic kidney diseaseVascular calcificationArterial calcificationOrphan diseaseCommon diseaseSequelae of diseaseEctopic vascular calcificationInternal elastic laminaPrevent mortalityRenal failureCardiac failureKidney diseaseSubcutaneous administrationRodent modelsAnimal modelsEctopic calcificationVascular wallLarge arteriesElastic laminaDiseaseCalcificationCalciphylaxisDecreased concentrationSclerosisArtery
2013
Molecular Basis of Purinergic Signal Metabolism by Ectonucleotide Pyrophosphatase/Phosphodiesterases 4 and 1 and Implications in Stroke*♦
Albright RA, Ornstein DL, Cao W, Chang WC, Robert D, Tehan M, Hoyer D, Liu L, Stabach P, Yang G, De La Cruz EM, Braddock DT. Molecular Basis of Purinergic Signal Metabolism by Ectonucleotide Pyrophosphatase/Phosphodiesterases 4 and 1 and Implications in Stroke*♦. Journal Of Biological Chemistry 2013, 289: 3294-3306. PMID: 24338010, PMCID: PMC3916532, DOI: 10.1074/jbc.m113.505867.Peer-Reviewed Original ResearchConceptsExtracellular membrane proteinsMembrane proteinsSubstrate specificityMolecular basisHigh-resolution crystal structuresResolution crystal structureComparative structural analysisATP hydrolysisNPP1Brain vascular endotheliumCorresponding regionTerminal phosphateLow nanomolar concentrationsPurinergic signalsPlatelet aggregationProteinATPEnzymeNanomolar concentrationsVascular endotheliumPhosphodiesterases 4Ap3AMetabolismSurface of chondrocytesTissue mineralization
2012
NPP4 is a procoagulant enzyme on the surface of vascular endothelium
Albright RA, Chang WC, Robert D, Ornstein DL, Cao W, Liu L, Redick ME, Young JI, De La Cruz EM, Braddock DT. NPP4 is a procoagulant enzyme on the surface of vascular endothelium. Blood 2012, 120: 4432-4440. PMID: 22995898, PMCID: PMC4017314, DOI: 10.1182/blood-2012-04-425215.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine DiphosphateAdultAnimalsBlood CoagulationCoagulantsCyclic Nucleotide Phosphodiesterases, Type 4Dinucleoside PhosphatesEndothelium, VascularFluorescent Antibody TechniqueHumansHydrolysisIn Vitro TechniquesInsectaPhosphoric Diester HydrolasesPlatelet AggregationPyrophosphatasesTissue DistributionConceptsPlatelet dense granule componentsNucleotide pyrophosphatase/phosphodiesteraseRelease of ADPUncharacterized enzymesPyrophosphatase/phosphodiesteraseGranule componentsEnzymatic basisRapid disaggregationDense granule releasePlatelet aggregationExtracellular spaceAp3AConcentration-dependent mannerEnzymeGranule releaseVascular endotheliumADPProcoagulant enzymeADP receptorActivationAggregationMutants
2011
Kinetic Analysis of Autotaxin Reveals Substrate-specific Catalytic Pathways and a Mechanism for Lysophosphatidic Acid Distribution*
Saunders LP, Cao W, Chang WC, Albright RA, Braddock DT, De La Cruz EM. Kinetic Analysis of Autotaxin Reveals Substrate-specific Catalytic Pathways and a Mechanism for Lysophosphatidic Acid Distribution*. Journal Of Biological Chemistry 2011, 286: 30130-30141. PMID: 21719699, PMCID: PMC3191052, DOI: 10.1074/jbc.m111.246884.Peer-Reviewed Original ResearchConceptsLysophosphatidic acidSecreted lysophospholipase DThr-210Synthase cycleVivo substrateSubstrate bindingQuantitative physiological modelsSignaling cascadesPosition 210LPA signalingCatalytic threonineFluorescent lipidLysophospholipase DCancer metastasisSlow catalysisCatalytic pathwayDiazol-4PathwayAutotaxinProduct releaseBindsLPA synthesisFS-3Acid distributionBioactive form
2010
Autotaxin and lipid signaling pathways as anticancer targets.
Braddock DT. Autotaxin and lipid signaling pathways as anticancer targets. Current Opinion In Investigational Drugs 2010, 11: 629-37. PMID: 20496257.Peer-Reviewed Original Research
2008
Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion
Saunders LP, Ouellette A, Bandle R, Chang WC, Zhou H, Misra RN, De La Cruz EM, Braddock DT. Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion. Molecular Cancer Therapeutics 2008, 7: 3352-3362. PMID: 18852138, PMCID: PMC7857123, DOI: 10.1158/1535-7163.mct-08-0463.Peer-Reviewed Original ResearchConceptsSmall molecule inhibitorsMelanoma cell migrationLysophosphatidic acidCell migrationRecombinant human proteinsChemical screenHuman proteinsATX levelsMalignant melanomaMigratory phenotypeMelanoma cell linesHuman melanoma cellsRole of autotaxinInvasion assaysLPA productionCell growthImmunohistochemistry of paraffinMolecular targetsCell linesATX inhibitorsAutotaxinMelanoma cellsHuman malignanciesEnzymatic productHuman tissues