Sp7 Mediated Control of Runx2 Function for Osteoblast Differentiation
Sp7介导的Runx2功能对成骨细胞分化的控制
基本信息
- 批准号:10359695
- 负责人:
- 金额:$ 35.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-03-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffinityAnatomyAnimalsBMP2 geneBiochemicalBiologicalBiological AvailabilityBiological ProcessBiologyBone DiseasesBone MatrixBone Morphogenetic ProteinsCalvariaCartilageCartilage DiseasesCell Differentiation processCell MaturationCell modelCellsChondrocytesChromatinCleidocranial DysplasiaCompetenceComplexCuesDNA BindingDNA Binding DomainDataDevelopmentDifferentiation and GrowthEmbryoErinaceidaeEventFailureFamilyFunctional disorderGene DeletionGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGoalsGrowthHumanIn Situ HybridizationInheritedInnovative TherapyInterventionKnockout MiceKnowledgeLinkMAP Kinase GeneMaintenanceMammalsMediatingMesenchymalMessenger RNAMetabolic Bone DiseasesModelingModificationMolecularMolecular BiologyMonitorMusMutagenesisMutationNull LymphocytesOsteoblastsOsteogenesisOsteogenesis ImperfectaPathway interactionsPatternPhenotypePhysiologic OssificationPost-Translational Protein ProcessingProcessProtein BiochemistryProteinsRBX1 geneRNARegulationResearchRoleRunx2 proteinSignal TransductionSkeletonSpecific qualifier valueSpecificitySubgroupSumoylation PathwayTestingTherapeutic InterventionTissuesTo specifyTooth eruptionVertebratesZinc Fingersbasebonebone cellbone repairembryo tissueexperimental studyimprovedin vivoinsightinterdisciplinary approachintramembranous bone formationmineralizationmorphogensmutantnovelosteoblast differentiationosteogenicosteoprogenitor cellpreventprotein functionreconstitutionrecruitrepairedskeletalskeletal disorderskeletal tissueskeletogenesisstable cell linetherapy developmenttranscription factortranscription regulatory networkubiquitin ligaseubiquitin mediated proteasome degradation
项目摘要
ABSTRACT: Development of skeleton in mammals is an exceedingly complex process. Completion of both
endochondral and intramembranous ossification entails a highly intricate but well-coordinated process of
patterning, cell fate commitment, differentiation, growth, and remodeling. These events are specified by a
coordinated temporal and spatial pattern of gene expression. At first, secreted morphogens such as
hedgehog, bone morphogenetic proteins, wingless proteins, and others, signal to key transcription factors
to specify gene expression. Runx2 is an essential transcription factor for both chondrocyte and osteoblast
differentiation. Runx2 gene deletion results in embryonic lethality due to a complete failure of bone
formation. In humans, mutation of the Runx2 gene causes cleidocranial dysplasia, a dominantly inherited
skeletal disorder. Another master regulator of skeletogenesis is the Specificity protein-7 (Sp7). Sp7 belongs
to the Sp subgroup of the Krüppel-like family of transcription factors characterized by three zinc-finger DNA-
binding domains. Deletion of Sp7 gene results in failure of osteoblasts, and bone formation. In humans,
mutation of the Sp7 gene is linked with the recessive form of osteogenesis imperfecta, skeletal fragility and
delayed tooth eruption. However, very little is known about the underlying molecular mechanism for the
surprisingly similar phenotype from the two seemingly unrelated proteins. Runx2 is required for the
expression of Sp7, as mice with targeted disruption of the Runx2 gene completely lack expression of Sp7.
In sharp contrast, the Runx2 expression is normal in the skeletal cells of Sp7 null animals. The functional
incompetency of Runx2 in the Sp7 null mice suggests that Sp7 presence is obligatory for completion of the
Runx2 osteogenic activity. It is important to note that the observation of Runx2 expression in Sp7 null mice
is limited to only RNA, determined by in situ hybridization of embryonic tissues. Our data show that despite
normal levels of Runx2 mRNA, Runx2 protein is highly unstable in skeletal tissues of Sp7 null mice. We
further demonstrate that Runx2 and Sp7 proteins form a molecular complex and their transcriptional activity
is regulated by unique posttranslational modifications. Our findings strongly suggest that in skeletal cells,
Sp7 acts as a molecular rheostat and is necessary for functional stability and turnover of Runx2 protein.
Our experiment will assess endogenous levels of Runx2 protein in Sp7 null background and by a regulated
and selective gene reconstitution in osteoprogenitor cells. The goal of this application is to identify and
define a) spatial and temporal organization and assembly of Runx2 and Sp7 regulatory complexes for the
formation and/or maintenance of osteoblasts and b) mechanisms supporting the stable complex formation
and retention of competency for skeletal gene expression. Knowledge obtained from this study will provide
molecular insights into components of a bone regulatory complex that can be targeted for innovative
therapy to improve cartilage and bone formation and repair.
摘要:哺乳动物骨骼发育是一个极其复杂的过程。两者的完成
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Amjad Javed其他文献
Amjad Javed的其他文献
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{{ truncateString('Amjad Javed', 18)}}的其他基金
Osteoblasts Role in Dysfunction of Body Adiposity and Bone Metabolism
成骨细胞在身体肥胖和骨代谢功能障碍中的作用
- 批准号:
10255860 - 财政年份:2020
- 资助金额:
$ 35.06万 - 项目类别:
Dental Academic Research Training Program (DART)
牙科学术研究培训计划 (DART)
- 批准号:
10207586 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Dental Academic Research Training Program (DART)
牙科学术研究培训计划 (DART)
- 批准号:
10657808 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Dental Academic Research Training Program (DART)
牙科学术研究培训计划 (DART)
- 批准号:
10207587 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Sp7 Mediated Control of Runx2 Function for Osteoblast Differentiation
Sp7介导的Runx2功能对成骨细胞分化的控制
- 批准号:
8220442 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Sp7 Mediated Control of Runx2 Function for Osteoblast Differentiation
Sp7介导的Runx2功能对成骨细胞分化的控制
- 批准号:
8611706 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Sp7 Mediated Control of Runx2 Function for Osteoblast Differentiation
Sp7介导的Runx2功能对成骨细胞分化的控制
- 批准号:
9981286 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Sp7 Mediated Control of Runx2 Function for Osteoblast Differentiation
Sp7介导的Runx2功能对成骨细胞分化的控制
- 批准号:
8427272 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Dental Academic Research Training Program (DART)
牙科学术研究培训计划 (DART)
- 批准号:
10657823 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
Dental Academic Research Training Program (DART)
牙科学术研究培训计划 (DART)
- 批准号:
10526909 - 财政年份:2012
- 资助金额:
$ 35.06万 - 项目类别:
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