The role of connective Tissue Growth Factor on BMP9-Induced Osteogenesis

结缔组织生长因子对 BMP9 诱导成骨的作用

• 批准号: 7316737
• 负责人: Hue Han Luu
• 金额: $ 11.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316737
• 关键词: Adenoviruses; Animal Model; Bone Development; Bone Morphogenetic Proteins; Bone Regeneration; Cell Line; Cells; Complex; Condition; Data; Development; Event; Extracellular Matrix Proteins; Fracture Healing; Goals; Green Fluorescent Proteins; In Vitro; Knowledge; Length; Mediating; Mesenchymal Stem Cells; Molecular; Numbers; Orthopedics; Osteogenesis; Pathway interactions; Patients; Process; Proteins; RNA Interference; Range; Regulation; Research Personnel; Role; Series; Small Interfering RNA; Testing; Tetracycline; Tetracyclines; Time; base; bone; bone healing; bone morphogenetic protein 9; clinical application; connective tissue growth factor; in vivo; mutant; precursor cell; programs; repaired; research study

DESCRIPTION (provided by applicant): Osteoblastic differentiation and bone formation is a well orchestrated cascade of events that is necessary for normal bone development and repair/fracture healing. The objective of this application is to characterize the role of Connective Tissue Growth Factor (CTGF) on osteoblastic differentiation and bone formation, with the ultimate goal of using BMP-9 and its downstream targets (e.g. CTGF), as bone regeneration agents in patients. CTGF is a secreted protein which has four distinct modules (domains) that share structural homology to several extracellular matrix proteins. Each module may have one or more distinct functions. We have found that CTGF expression is consistently upregulated early in the pathway of Bone Morphogenetic Protein (BMP)-induced osteoblastic differentiation. Several BMPs, especially BMP9, have been shown to be potent stimulators of osteoblastic differentiation and bone formation. Interestingly, temporal regulation of CTGF expression may be essential for BMP-induced osteoblastic differentiation. In order to further understand the molecular events regulating osteogenic lineage-specific differentiation of mesenchymal stem cell and bone formation, we propose a series of hypothesis-driven experiments that will determine the role of CTGF in this well-orchestrated process. Specifically, we will determine: (1) whether specific modules of CTGF and temporal expression of CTGF regulate BMP9-induced osteoblastic differentiation in vitro; (2) if CTGF regulates BMP9-induced bone formation in a heterotopic bone formation animal model; and (3) whether temporally controlled CTGF silencing by RNA interference (RNAi)-mediated knockdown modulates BMP9-induced osteoblastic differentiation in vitro, and heterotopic bone formation in vivo. Knowledge gained from these sets of experiments will expand our understanding of the role of BMPs and CTGF on osteogenic differentiation of mesenchymal stem cells and bone formation. Both BMPs and their downstream targets, like CTGF, can have a broad range of clinical applications in a number of orthopaedic conditions, such as enhancing recalcitrant fracture healing or promoting bone regeneration in patients. LAY STATEMENT: In normal development and bone healing, there is a well-orchestrated process of stimulating precursor cells to become bone-forming cells, and the eventual formation of bone. This proposal examines the function of an important factor (Connective Tissue Growth Factor) in this complex process of bone formation, with the goal of its application in fracture healing and bone regeneration in patients.

描述(申请人提供)：成骨细胞分化和骨形成是一系列精心安排的事件，对于正常的骨骼发育和修复/骨折愈合是必要的。本应用的目的是确定结缔组织生长因子(CTGF)在成骨细胞分化和骨形成中的作用，最终目的是将BMP-9及其下游靶点(例如CTGF)用作患者的骨再生剂。CTGF是一种分泌型蛋白质，它有四个不同的模块(结构域)，与几种细胞外基质蛋白具有相同的结构同源性。每个模块可以具有一个或多个不同的功能。我们发现，在骨形态发生蛋白(BMP)诱导成骨细胞分化的早期，CTGF的表达持续上调。一些BMP，特别是BMP9，已被证明是成骨细胞分化和骨形成的有力刺激因素。有趣的是，CTGF表达的时间调控对于BMP诱导的成骨细胞分化可能是必不可少的。为了进一步了解调控间充质干细胞成骨分化和骨形成的分子事件，我们提出了一系列假设驱动的实验，以确定CTGF在这一精心安排的过程中的作用。具体地说，我们将确定：(1)特定的CTGF模块和CTGF的瞬时表达是否在体外调控BMP9诱导的成骨细胞分化；(2)在异位成骨动物模型中，CTGF是否调控BMP9诱导的成骨细胞形成；以及(3)通过RNA干扰(RNAi)介导的基因敲除来时间控制CTGF沉默是否调控BMP9诱导的成骨细胞分化和体内的异位成骨形成。从这些实验中获得的知识将扩大我们对BMPs和CTGF在间充质干细胞成骨分化和骨形成中的作用的理解。BMP及其下游靶点，如CTGF，可在许多骨科疾病中有广泛的临床应用，如增强顽固性骨折愈合或促进患者的骨再生。 Lay声明：在正常发育和骨愈合过程中，有一个精心安排的过程，刺激前体细胞成为骨形成细胞，并最终形成骨。本研究旨在研究结缔组织生长因子在这一复杂的骨形成过程中的作用，以期将其应用于骨折愈合和患者的骨再生。