The Mechanism of TGFBR2 Action in Joint Degeneration.

描述（由申请人提供）：骨关节炎是工业化世界致残的主要原因，但几乎不知道与骨关节炎相关的软骨破坏机制。人体内的大多数骨骼都是通过软骨内成骨的过程形成的，在这个过程中，首先形成软骨模型，然后用骨头代替。虽然大多数软骨模型是短暂的，但有几个部位的成熟软骨持续存在，包括关节软骨，这是正常关节功能所必需的。小鼠基因操作的最新进展导致了新的动物模型和新的概念，这与理解人类骨关节炎有关。我实验室的长期目标是了解介导关节软骨发育、持续和修复的因素，并确定骨关节炎预防和治疗策略的特定靶点。TGF-b是一种多功能肽，已被证明可调节细胞分化和组织特异性基因表达。之前，我们在关节软骨、骨膜/软骨膜和滑膜中产生了表达TGF-b型II受体（Tgfbr2）显性阴性突变的转基因小鼠。这些细胞类型对TGF-b的反应性改变导致类似于人类骨关节炎的进行性骨骼疾病。骨关节炎症状出现之前，软骨细胞周围的细胞周基质减少，软骨细胞不适当的肥大分化。数据表明，TGF-b通常可以防止关节退变，然而，TGF-b在关节软骨中的下游效应尚不清楚。本研究的目的是表征一种新的关节退变小鼠模型，该模型可用于确定TGF-b在关节软骨维持和修复中的作用机制。提出以下目标：在小鼠出生后软骨中诱导和条件缺失Tgfbr2。通过将基因表达谱与野生型和Col2aCreER关节退变的发生和进展相关联，提出TGF-b在关节软骨中的作用机制的具体假设；Tgfbr2lox/lox小鼠，通过鉴定关节软骨中TGF-b信号的下游效应物。未来的研究将确定选定的tgf -b调节基因在维持软骨表型中的作用。公共卫生相关性。骨关节炎是最常见的关节炎形式，也是工业化世界中肌肉骨骼残疾的主要原因。我们的初步数据和其他实验室的结果表明，TGF-b信号在软骨稳态和修复中起着关键作用，然而，对TGF-b在关节软骨中的作用的分子机制知之甚少。我们建议在关节软骨中确定TGF-b信号的下游靶点，这些靶点可以作为预防和治疗骨关节炎的特异性治疗靶点。

DESCRIPTION (provided by applicant): Osteoarthritis is the leading cause of disability in the industrialized world but almost nothing is known about mechanisms of cartilage destruction associated with osteoarthritis. Most of the bones in the body develop by a process called endochondral bone formation in which a cartilage model is made first and then replaced with bone. Although most of the cartilage model is transient, there are several sites where mature cartilage persists including the articular cartilage, which is required for proper joint function. Recent advances in the genetic manipulation of mice have lead to new animal models and new concepts that are relevant to understanding osteoarthritis in humans. The long-term objective of my laboratory is to understand the factors that mediate the development, persistence, and repair of articular cartilage and to identify specific targets for prevention and treatment strategies for osteoarthritis. TGF-b is a multifunctional peptide that has been shown to regulate cellular differentiation and tissue-specific gene expression. Previously, we generated transgenic mice that express a dominant-negative mutation of the TGF-b type II receptor (Tgfbr2) in articular cartilage, periosteum/ perichondrium, and synovium. Altered responsiveness to TGF-b in these cell types resulted in a progressive skeletal disease that resembled osteoarthritis in humans. Osteoarthritis symptoms were preceded by both a decrease in the pericellular matrix surrounding chondrocytes and inappropriate hypertrophic differentiation of chondrocytes. The data suggest that TGF-b normally prevents joint degeneration, however, the downstream effectors of TGF-b in the articular cartilage are not known. The objective of this study is to characterize a new mouse model of joint degeneration that can be used to determine the mechanism of TGF-b action in maintenance and repair of articular cartilage. The following aims are proposed: 1. To characterize mice with an inducible and conditional deletion of Tgfbr2 in post-natal cartilage and 2. To develop specific hypotheses about the mechanism of TGF-b action in articular cartilage by correlating gene expression profiles with the onset and progression of joint degeneration in wild type and Col2aCreER;Tgfbr2lox/lox mice and by identifying downstream effectors of TGF-b signaling in articular cartilage. Future studies will determine the role of selected TGF-b-regulated genes in maintaining the cartilage phenotype. PUBLIC HEALTH RELEVANCE. Osteoarthritis is the most common form of arthritis and the leading cause of musculoskeletal disability in the industrialized world. Our preliminary data and results from other laboratories suggest that TGF-b signaling has a critical role in cartilage homeostasis and repair, nevertheless, very little is know about the molecular mechanism of TGF-b action in articular cartilage. We propose to identify downstream targets of TGF-b signaling in articular cartilage that can be used as specific therapeutic targets for prevention and treatment of osteoarthritis.