Beta-Catenin Signaling and Pathogenesis of Osteoarthritis

β-连环蛋白信号传导和骨关节炎的发病机制

基本信息

  • 批准号:
    8515334
  • 负责人:
  • 金额:
    $ 31.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-01 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a degenerative joint disease and the mechanism of this disease is poorly understood. The articular chondrocyte is the only cell type in articular cartilage and these cells are responsible for maintaining the appropriate structure and function of the articular cartilage tissue. The function of articular chondrocytes is regulated by a variety of growth factors, including Wnt family members. Recent human genetic studies demonstrate that patients with a mutation (Arg324Gly substitution) in the secreted frizzled-related protein 3 (sFRP3), a Wnt signaling inhibitor, have a predisposition for the development of OA. It is also known that the mutation of sFRP3 causes activation of ¿-catenin signaling. These findings suggest that the canonical Wnt/¿-catenin signaling pathway may play a critical role during the development of OA. However, direct genetic and molecular evidence for the role of ¿-catenin in the development of OA has not been reported before. In preliminary studies, we demonstrated that ¿-catenin conditional activation (cAct) mice developed a severe OA-like phenotype. We also found that meniscus injury and mechanical injury, which often lead to the development of OA, activate canonical Wnt/¿-catenin signaling in articular chondrocytes. The underlying hypotheses of this proposal are that 1) canonical Wnt/¿-catenin signaling plays a key role and is required for sensing changes in meniscus injury and mechanical injury in articular chondrocytes and its abnormal activation will lead to the development of an OA-like phenotype; and 2) Bmp2 and Mmp13 are key downstream target genes of ¿-catenin signaling in articular chondrocytes and deletion of these genes will significantly reverse the OA-like phenotype observed in ¿-catenin cAct mice. In Specific Aim 1, we will analyze ¿-catenin cAct mice and determine the age-dependent OA-like phenotype in adult ¿-catenin cAct mice. Changes in articular cartilage structure and morphology and articular chondrocyte function will be examined in 3-, 6-, 9-, and 12-month-old ¿-catenin cAct mice. In addition, we will also determine if adult ¿-catenin cAct mice are more susceptible to chemically- or joint injury-induced OA. In Specific Aim 2, we will determine the role of meniscus injury or mechanical injury in activation of ¿-catenin signaling and the development of OA. We will determine if activation of the canonical Wnt/¿-catenin signaling is required for the meniscus injury- or mechanical injury-induced OA-like phenotype in articular chondrocytes. In Specific Aim 3, we will determine if Bmp2 and Mmp-13 are key downstream mediators of ¿-catenin signaling during the development of OA in adult ¿-catenin cAct mice. We will delete the Bmp2 or Mmp-13 gene in articular chondrocytes where the ¿-catenin gene is over expressed and determine if their deletion will significantly reverse the OA-like phenotype observed in ¿-catenin cAct mice. Our proposed studies will provide novel and definitive evidence about the role of ¿-catenin signaling in articular chondrocyte function and OA pathogenesis.
描述(由申请人提供):骨关节炎(OA)是一种退行性关节疾病,这种疾病的机制尚不清楚。关节软骨细胞是关节软骨中唯一的细胞类型,这些细胞负责维持关节软骨组织的适当结构和功能。关节软骨细胞的功能受多种生长因子调控,包括Wnt家族成员。最近的人类遗传学研究表明,分泌的卷曲相关蛋白3 (sFRP3)(一种Wnt信号抑制剂)发生突变(Arg324Gly替代)的患者易患OA。我们还知道,sFRP3的突变会导致¿-catenin信号的激活。这些发现表明,典型的Wnt/¿-catenin信号通路可能在OA的发展过程中发挥关键作用。然而,直接的遗传和分子证据表明¿-catenin在OA的发展中所起的作用,以前没有报道过。在初步研究中,我们证明了¿-catenin条件激活(cAct)小鼠产生了严重的oa样表型。我们还发现,通常导致OA发生的半月板损伤和机械损伤可激活关节软骨细胞中典型的Wnt/¿-catenin信号。本研究的基本假设是:1)典型的Wnt/¿-catenin信号在半月板损伤和关节软骨细胞机械损伤的感知变化中起关键作用,其异常激活将导致oa样表型的发展;2) Bmp2和Mmp13是关节软骨细胞中¿-catenin信号传导的关键下游靶基因,这些基因的缺失将显著逆转¿-catenin cAct小鼠中观察到的a样表型。在Specific Aim 1中,我们将分析¿-catenin cAct小鼠,并确定成年¿-catenin cAct小鼠的年龄依赖性oa样表型。在3、6、9和12个月大的-catenin cAct小鼠中检测关节软骨结构和形态以及关节软骨细胞功能的变化。此外,我们还将确定成年¿-catenin cAct小鼠是否更容易受到化学或关节损伤引起的OA。在Specific Aim 2中,我们将确定半月板损伤或机械损伤在¿-catenin信号激活和OA发展中的作用。我们将确定典型的Wnt/¿-catenin信号的激活是否需要半月板损伤或机械损伤诱导的关节软骨细胞的oa样表型。在Specific Aim 3中,我们将确定Bmp2和Mmp-13是否是成年-catenin cAct小鼠OA发展过程中-catenin信号传导的关键下游介质。我们将在过度表达-catenin基因的关节软骨细胞中删除Bmp2或Mmp-13基因,并确定它们的删除是否会显著逆转在-catenin cAct小鼠中观察到的oa样表型。我们提出的研究将为¿-catenin信号在关节软骨细胞功能和OA发病机制中的作用提供新的和明确的证据。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation.
使用带有明胶微球的壳聚糖凝胶顺序递送BMP-2和IGF-1可以增强早期成骨细胞分化。
  • DOI:
    10.1016/j.actbio.2012.01.009
  • 发表时间:
    2012-05
  • 期刊:
  • 影响因子:
    9.7
  • 作者:
    Kim, Sungwoo;Kang, Yunqing;Krueger, Chad A.;Sen, Milan;Holcomb, John B.;Chen, Di;Wenke, Joseph C.;Yang, Yunzhi
  • 通讯作者:
    Yang, Yunzhi
Beta-catenin, cartilage, and osteoarthritis.
Mice Deficient in NF-κB p50 and p52 or RANK Have Defective Growth Plate Formation and Post-natal Dwarfism.
  • DOI:
    10.4248/br201304004
  • 发表时间:
    2013-12
  • 期刊:
  • 影响因子:
    12.7
  • 作者:
    Xing L;Chen D;Boyce BF
  • 通讯作者:
    Boyce BF
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DI CHEN其他文献

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{{ truncateString('DI CHEN', 18)}}的其他基金

The Role of MicroRNA in Osteoarthritis
MicroRNA 在骨关节炎中的作用
  • 批准号:
    9317937
  • 财政年份:
    2017
  • 资助金额:
    $ 31.08万
  • 项目类别:
Allosteric Small Molecule Inhibitor Of Nerve Growth Factor Signaling in Low Back Pain
腰痛神经生长因子信号传导的变构小分子抑制剂
  • 批准号:
    9146276
  • 财政年份:
    2015
  • 资助金额:
    $ 31.08万
  • 项目类别:
Pain Mechanisms of Knee Joint Osteoarthritis
膝关节骨关节炎的疼痛机制
  • 批准号:
    9068662
  • 财政年份:
    2012
  • 资助金额:
    $ 31.08万
  • 项目类别:
Beta-Catenin Signaling and Pathogenesis of Osteoarthritis
β-连环蛋白信号传导和骨关节炎的发病机制
  • 批准号:
    7740673
  • 财政年份:
    2009
  • 资助金额:
    $ 31.08万
  • 项目类别:
Beta-Catenin Signaling and Pathogenesis of Osteoarthritis
β-连环蛋白信号传导和骨关节炎的发病机制
  • 批准号:
    8091321
  • 财政年份:
    2009
  • 资助金额:
    $ 31.08万
  • 项目类别:
Beta-Catenin Signaling and Pathogenesis of Osteoarthritis
β-连环蛋白信号传导和骨关节炎的发病机制
  • 批准号:
    7884592
  • 财政年份:
    2009
  • 资助金额:
    $ 31.08万
  • 项目类别:
Beta-Catenin Signaling and Pathogenesis of Osteoarthritis
β-连环蛋白信号传导和骨关节炎的发病机制
  • 批准号:
    8286054
  • 财政年份:
    2009
  • 资助金额:
    $ 31.08万
  • 项目类别:
Beta-Catenin Signaling and Pathogenesis of Osteoarthritis
β-连环蛋白信号传导和骨关节炎的发病机制
  • 批准号:
    8442145
  • 财政年份:
    2009
  • 资助金额:
    $ 31.08万
  • 项目类别:
TGF-beta Signaling and Degenerative Joint Diseases
TGF-β 信号传导和退行性关节疾病
  • 批准号:
    9113344
  • 财政年份:
    2007
  • 资助金额:
    $ 31.08万
  • 项目类别:
TGF-? Signaling and Degenerative Joint Diseases
转化生长因子-?
  • 批准号:
    8689718
  • 财政年份:
    2007
  • 资助金额:
    $ 31.08万
  • 项目类别:

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