Roles of Inhibitory Smads in Endochondral Bone Formation

抑制性 Smad 在软骨内骨形成中的作用

• 批准号: 8129718
• 负责人: Kristine David Estrada
• 金额: $ 3.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-08-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129718
• 关键词: ARNT gene; Academy; Accounting; Address; Affect; American; Apoptosis; Apoptotic; Arthritis; BMP2 gene; Bone Morphogenetic Proteins; Cartilage; Cellular Stress; Chondrocytes; Chondrogenesis; Clinic; Complex; Data; Dose; Effectiveness; Epiphysial cartilage; Equilibrium; Erinaceidae; Evaluation; Exhibits; Extracellular Matrix; Feedback; Fibroblast Growth Factor; Gene Expression; Goals; Human; Hypertrophy; Hypoxia; In Vitro; Inhibin-beta Subunits; Inhibitory Smad Protein; Lead; Ligands; Limb structure; Link; Maintenance; Mediating; Mus; Musculoskeletal Diseases; Mutation; Orthopedics; Osteogenesis; Pathway interactions; Pattern; Physiological; Prevalence; Process; Proteins; Recombinants; Regulation; Repression; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Surgeon; System; Testing; Tissues; Transforming Growth Factor beta; United States; abstracting; activating transcription factor 3; bone morphogenetic protein receptors; cartilage regeneration; cartilage repair; disability; economic cost; endoplasmic reticulum stress; extracellular; in vitro testing; in vivo; inhibitor/antagonist; loss of function; mutant; parathyroid hormone-related protein; programs; protein expression; receptor; repaired; transcription factor; transforming growth factor beta3

Project Summary/Abstract Endochondral ossification involves a highly coordinated program of chondrocyte differentiation, proliferation, maturation and hypertrophy. The cellular activities of chondrocytes are organized in distinct zones in the growth plate, making this tissue uniquely suited for in vivo studies, as effects of mutations can be linked to specific cellular activities. The bone morphogenetic protein (BMP) and transforming growth factor beta (TGFbeta)/activin pathways are important regulators of these processes. The importance of extracellular antagonists as regulators of the duration, intensity and extent of BMP and TGFbeta/activin signaling has been defined. For example, mice lacking the BMP receptor antagonist Noggin exhibit cartilage overgrowth concurrent with excess BMP activity. However, very little is known about the roles of intracellular inhibitors of BMP and TGFbeta/activin pathways, such as the inhibitory Smad (I-Smad) proteins, Smad6 and Smad7. Gain and loss of function studies have revealed potential roles for I-Smads in chondrocytes in vitro, but no in vivo studies have been performed. The long-term goal of this project is to understand how intracellular regulation of BMP and TGFbeta/activin signaling by I-Smads controls chondrogenesis as a prerequisite to more efficient strategies utilizing BMPs to achieve cartilage maintenance and repair. To achieve this goal, it is important to determine whether I-Smads are critical for chondrogenesis and to identify specific aspects of chondrogenesis, as well as mechanisms, impacted by I-Smads. Hence, the specific hypotheses to be addressed in this proposal are (1) I-Smads are essential for normal endochondral bone formation, (2) loss of I-Smads impacts the balance of signaling cross-talk between TGFbeta/activin and BMP pathways in the growth plate that will affect the progression of endochondral ossification, and (3) TGFbeta signaling interact via Smad7 with key survival/stress pathways in the growth plate.

项目摘要/摘要 软骨内骨化涉及软骨细胞分化、增殖、成熟和肥大的高度协调过程。软骨细胞的细胞活动在生长板的不同区域中组织，使这种组织特别适合体内研究，因为突变的影响可以与特定的细胞活动联系在一起。骨形态发生蛋白(BMP)和转化生长因子β(TGFβ)/激活素通路是这些过程的重要调节因子。细胞外拮抗剂作为骨形态发生蛋白和转化生长因子β/激活素信号的持续时间、强度和程度的调节剂的重要性已经被定义。例如，缺乏BMP受体拮抗剂Noggin的小鼠表现出软骨过度生长，同时BMP活性过高。然而，关于BMP和TGFbeta/激活素途径的细胞内抑制物，如抑制性Smad(I-Smad)蛋白、Smad6和Smad7的作用，人们知之甚少。功能获得和功能丧失的研究已经揭示了I-Smads在体外对软骨细胞的潜在作用，但还没有进行体内研究。该项目的长期目标是了解I-Smads对BMP和TGFbeta/激活素信号的细胞内调控是如何控制软骨形成的，这是利用BMP实现软骨维护和修复的更有效策略的先决条件。为了实现这一目标，重要的是确定i-Smads是否对软骨形成至关重要，并确定i-Smads影响软骨形成的特定方面以及机制。因此，本研究拟提出的具体假设是：(1)I-Smads对于正常的软骨内骨形成是必不可少的；(2)I-Smads的缺失影响生长板中TGFbeta/激活素和BMP信号通路之间的信号串扰平衡，从而影响软骨内成骨的进程；(3)TGFbeta信号通过Smad7与生长板中的关键生存/应激通路相互作用。