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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：
Amjad Javed
金额：
$ 35.06万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
https://reporter.nih.gov/project-details/10359695
关键词：
Address Affinity Anatomy Animals BMP2 gene Biochemical Biological Biological Availability Biological Process Biology Bone Diseases Bone Matrix Bone Morphogenetic Proteins Calvaria Cartilage Cartilage Diseases Cell Differentiation process Cell Maturation Cell model Cells Chondrocytes Chromatin Cleidocranial Dysplasia Competence Complex Cues DNA Binding DNA Binding Domain Data Development Differentiation and Growth Embryo Erinaceidae Event Failure Family Functional disorder Gene Deletion Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Growth Human In Situ Hybridization Inherited Innovative Therapy Intervention Knockout Mice Knowledge Link MAP Kinase Gene Maintenance Mammals Mediating Mesenchymal Messenger RNA Metabolic Bone Diseases Modeling Modification Molecular Molecular Biology Monitor Mus Mutagenesis Mutation Null Lymphocytes Osteoblasts Osteogenesis Osteogenesis Imperfecta Pathway interactions Pattern Phenotype Physiologic Ossification Post-Translational Protein Processing Process Protein Biochemistry Proteins RBX1 gene RNA Regulation Research Role Runx2 protein Signal Transduction Skeleton Specific qualifier value Specificity Subgroup Sumoylation Pathway Testing Therapeutic Intervention Tissues To specify Tooth eruption Vertebrates Zinc Fingers base bone bone cell bone repair embryo tissue experimental study improved in vivo insight interdisciplinary approach intramembranous bone formation mineralization morphogens mutant novel osteoblast differentiation osteogenic osteoprogenitor cell prevent protein function reconstitution recruit repaired skeletal skeletal disorder skeletal tissue skeletogenesis stable cell line therapy development transcription factor transcription regulatory network ubiquitin ligase ubiquitin 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