Extracellular remodeling in bone development and repair

骨发育和修复中的细胞外重塑

基本信息

批准号：
7568909
负责人：
ZENA WERB
金额：
$ 32.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7568909
关键词：
Ablation Adult Apoptosis Apoptotic Area Biochemical Blood Vessels Bone Development Bone Marrow Bone remodeling Calcified Cartilage Cell Death Cells Cessation of life Chondrocytes Coupled Defect Deposition Development Differentiation and Growth Endothelial Cells Environment Enzymes Epiphysial cartilage Event Extracellular Matrix Extracellular Matrix Proteins Feeds Fracture Fracture Healing Funding Gelatinase B Goals Growth Healed Hypertrophy Injury Lesion Matrix Metalloproteinases Mechanics Mediating Modeling Molecular Molecular Genetics Morphogenesis Mus Mutant Strains Mice Mutation Natural regeneration Osteoblasts Osteoclasts Osteogenesis Pathway interactions Physiological Process Proliferating Proteolysis Recruitment Activity Regulation Regulation of Proteolysis Relative (related person)Rest Role Skeletal Development Therapeutic Intervention Tissues Transplantation Vascular Endothelial Growth Factors Wild Type Mouse angiogenesis bone cell growth cell type collagenase 3 extracellular healing insight intramembranous bone formation long bone novel osteogenic osteoprogenitor cell progenitor programs regenerative repaired response skeletal skeletal injury skeletal regeneration substantia spongiosa therapy development tool

项目摘要

Endochondral ossification is a pivotal event in skeletal development and in adult skeletal regeneration. In both, osteoclasts and chondroclasts erode hypertrophic cartilage, hypertrophic chondrocyte die, blood vessels grow in followed by recruitment of osteoprogenitor cells and bone and bone marrow cavity formation. These events require extracellular proteolysis and are essential for normal bone formation and repair. The goal of this proposal is to elucidate the molecular and cellular mechanisms, controlled by matrix metalloproteinases (MMPs), that co-ordinate the events in endochondral bone formation and regeneration. In the previous funding period we showed that proteolysis by MMP-9 is a critical determinant of the events in endochondral bone formation. MMP-9 and vascular endothelial growth factor (VEGF) act in overlapping pathways to regulate the program of hypertrophic cartilage remodeling, angiogenesis and bone formation in growth plate development and skeletal regeneration. We now propose to use genetic, molecular and cell Diological approaches to further characterize how these two MMPs, each separately and together, regulate the program of endochondral bone development. We will use targeted and conditional mutations in mice to evaluate the relative roles various cell types expressing MMP-9 and MMP-13 (collagenase-3) to cartilage emodeling, osteoblast and osteoclast function, vascular recruitment and skeletal remodeling, using morphometric and biochemical approaches coupled with cell and organotypic cultures. From these studies we will be able to determine the steps in skeletal growth plate morphogenesis. We will focus on terminal differentiation of hypertrophic chondrocytes, extracellular matrix remodeling, regulation of vascular recruitment and bone remodeling. We will then use the MMP mutant mice and unstable and stabilized fractures as tools to evaluate how the mechanical environment determines the regenerative response during in skeletal regeneration in wild type and mutant mice. We will then build on these analyses to determine the physiologic substrates of the MMPs during development and skeletal repair. These studies will give us insights into novel and important functions for the MMPs, extracellular matrix proteins and angiogenic regulators in endochondral bone formation. The endochondral ossification processes are misregulated in osteparthritis and recalcitrant hard tissue lesions. A fuller understanding of the central role of angiogenesis gjnd its regulation by proteolysis in these processes may have implications for therapeutic interventions and the development of therapy for certain types of non-healing fractures.

软骨内骨化是骨骼发育和成人骨骼再生的关键事件。在破骨细胞和破软骨细胞都会侵蚀肥大的软骨，肥大的软骨细胞死亡，血液血管生长，随后骨祖细胞募集以及骨和骨髓腔形成。这些事件需要细胞外蛋白水解，对于正常的骨形成和修复至关重要。这该提案的目标是阐明由基质控制的分子和细胞机制金属蛋白酶（MMP），协调软骨内骨形成和再生的事件。在在之前的资助期间，我们表明 MMP-9 的蛋白水解是事件的关键决定因素软骨内骨形成。 MMP-9 和血管内皮生长因子 (VEGF) 重叠发挥作用调节肥大软骨重塑、血管生成和骨形成程序的途径生长板发育和骨骼再生。我们现在建议使用遗传、分子和细胞对话方法进一步描述这两种 MMP 如何单独和共同调节软骨内骨发育计划。我们将利用小鼠的定向和条件突变来评估表达 MMP-9 和 MMP-13（胶原酶-3）的各种细胞类型对软骨的相对作用建模、成骨细胞和破骨细胞功能、血管募集和骨骼重塑，使用形态测定和生化方法与细胞和器官培养相结合。从这些研究来看我们将能够确定骨骼生长板形态发生的步骤。我们将专注于终端肥大软骨细胞分化、细胞外基质重塑、血管调节募集和骨重塑。然后我们将使用 MMP 突变小鼠以及不稳定和稳定的小鼠骨折作为评估机械环境如何决定再生响应的工具野生型和突变型小鼠的骨骼再生。然后我们将在这些分析的基础上确定发育和骨骼修复过程中 MMP 的生理底物。这些研究将为我们提供深入了解 MMP、细胞外基质蛋白和血管生成的新颖且重要的功能软骨内骨形成的调节因子。软骨内骨化过程被错误调节骨关节炎和顽固性硬组织病变。更全面地了解血管生成的核心作用 Gjnd 在这些过程中通过蛋白水解进行调节可能对治疗干预和治疗产生影响某些类型的不愈合骨折的治疗方法的开发。