CSF-1 Gene Expression in Osteoclast Biology

破骨细胞生物学中的 CSF-1 基因表达

基本信息

项目摘要

ABSTRACT Bone loss and fracture are leading causes of morbidity with aging. The mechanisms of age-related bone disease have not been defined. Our studies suggest that CSF-1 deficiency and increased Nox4 oxidase expression in osteocytes are key determinants of oxidant stress that impact osteocyte survival/function that is essential for bone remodeling. The long-term goal of this proposal is to delineate mechanistic pathways by which CSF-1/oxidative stress regulate osteocyte homeostasis and identify therapeutic targets to prevent bone loss with age. CSF-1 and CSF-1R are expressed by osteocytes. The mechanisms by which CSF-1 or its isoforms, soluble (s) and cell-surface (cs) CSF-1, regulate osteocyte survival/function have not been explored. Oxidative stress contributes to osteocyte demise and bone loss with aging. Our findings indicate that, with aging, CSF-1 expression declines in osteocytes. We generated mice with global CSF-1 deficiency (CSF-1KO) that show osteopetrosis with increased fractures and osteocyte defects including apoptosis, associated with increased NADPH oxidase Nox4 expression/activity and reduced Cx43 expression. CSF-1 decreases NADPH oxidase activity in cultured osteocytes and CSF-1KO bone osteocytes show elevated Nox4 and activation of the mTOR pathway compared to WT osteocytes, suggesting that CSF-1 protects from oxidant stress. DMP1Cre-CSF-1cKO mice with conditional knockout (cKO) of CSF-1 in osteocytes/late osteoblasts also show increased Nox4, osteocyte defects, reduced osteoclasts and bone formation, predisposing to bone loss and fracture with age. We hypothesize that: a) osteocyte cKO of CSF-1 increases Nox4 and oxidative stress, impairs osteocytes and accelerates bone defects with age, b) deletion of Nox4 in CSF-1cKO osteocytes decreases oxidative stress, restores osteocyte function/bone remodeling with age, c) expression of sCSF-1 in CSF-1cKO osteocytes promotes osteocyte survival and proper bone remodeling to a greater extent than csCSF-1 during aging. We will test these hypotheses in the following specific aims: 1) Determine the effect of CSF-1cKO in osteocytes on bone phenotype and redox state during aging. WT and CSF-1cKO mice will be examined for bone phenotype and osteocytes will be assessed for apoptosis, Nox4 and gene expression profile; 2) Determine the role of Nox4 in osteocytes of CSF-1cKO mice and mechanisms by which CSF-1 regulates osteocyte survival. To dissect the interplay between CSF-1 and Nox4, mice with cKO of CSF-1 and Nox4 in osteocytes will be generated and signaling mechanisms by which CSF-1 regulates osteocyte survival will be analyzed in cultured osteocytes; 3) Determine the ability of CSF-1 isoforms to rescue bone defects in CSF-1cKO mice. This will be accomplished using a transgenic approach to target sCSF-1 or csCSF-1 in osteocytes of CSF-1cKO mice. These studies will provide new mechanistic insights by which CSF-1 controls osteocyte survival/function and may lead to novel therapeutic strategies for improving osteocyte viability crucial for bone strength and longevity.
摘要 随着年龄的增长,骨丢失和骨折是发病率的主要原因。增龄相关骨的发生机制 疾病还没有被定义。我们的研究表明,脑脊液-1缺乏和NOX4氧化酶增加 骨细胞的表达是影响骨细胞存活/功能的氧化应激的关键决定因素 对于骨骼重塑来说是必不可少的。这项提议的长期目标是描绘机械化的道路 脑脊液-1/氧化应激调控骨细胞动态平衡并确定防治靶点 随着年龄的增长,骨丢失。CSF-1和CSF-1R主要由骨细胞表达。CSF-1或Csf-1的机制 其异构体--可溶性(S)和细胞表面(Cs)脑脊液-1调节骨细胞存活/功能的研究尚未见报道 探索过了。随着年龄的增长,氧化应激会导致骨细胞死亡和骨质流失。我们的发现表明 随着年龄的增长,骨细胞中CSF-1的表达下降。我们产生了全球范围内缺乏脑脊液-1的小鼠 (CSF-1KO),显示骨化病伴骨折增加和骨细胞缺陷,包括细胞凋亡, 与NADPH氧化酶NOX4表达/活性增加和Cx43表达降低有关。脑脊液-1 降低培养骨细胞中NADPH氧化酶活性,而CSF-1KO骨细胞活性升高 与WT骨细胞相比,NOX4和mTOR通路的激活,表明CSF-1具有保护作用 氧化应激所致。骨细胞条件基因敲除的DMP1Cre-CSF-1cKO小鼠/晚期 成骨细胞还表现为NOX4增加,骨细胞缺陷,破骨细胞和骨形成减少, 随年龄增长易发生骨质流失和骨折。我们假设:a)CSF-1的骨细胞CKO增加 NOX4和氧化应激,损伤骨细胞,加速骨缺损,随着年龄的增长,b)NOX4在 Csf-1cKO骨细胞减少氧化应激,恢复骨细胞功能/骨改建,随年龄增长,c) SCSF-1在CSF-1cKO骨细胞中的表达促进骨细胞存活和适当的骨重建 在衰老过程中,其变化幅度大于csCSF-1。我们将在以下具体目标上检验这些假设:1) 测定骨细胞中CSF-1cKO对衰老过程中骨表型和氧化还原状态的影响。WT和 将对CSF-1cKO小鼠进行骨表型检查,并对骨细胞进行凋亡评估,NOX4 和基因表达谱;2)确定NOX4在CSF-1cKO小鼠骨细胞中的作用 CSF-1调控骨细胞存活的机制。剖析脑脊液-1与脑脊液的相互作用 NOX4,骨细胞中CKO-CSF-1和NOX4的小鼠将被产生并通过 将在培养的骨细胞中分析哪些CSF-1调节骨细胞的存活;3)确定 CSF-1亚型用于修复CSF-1cKO小鼠骨缺损。这将通过转基因技术完成。 CSF1cKO小鼠骨细胞靶向sCSF-1或csCSF-1的探讨这些研究将提供新的 CSF-1控制骨细胞存活/功能并可能导致新的治疗方法的机制洞察 提高骨细胞活性的策略对骨骼强度和寿命至关重要。

项目成果

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SHERRY L ABBOUD-WERNER其他文献

SHERRY L ABBOUD-WERNER的其他文献

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{{ truncateString('SHERRY L ABBOUD-WERNER', 18)}}的其他基金

CSF-1 Gene Expression in Osteoclast Biology
破骨细胞生物学中的 CSF-1 基因表达
  • 批准号:
    8741919
  • 财政年份:
    2013
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 Gene Expression in Osteoclast Biology
破骨细胞生物学中的 CSF-1 基因表达
  • 批准号:
    8885628
  • 财政年份:
    2013
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    8294405
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    7008827
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    7173911
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    7527520
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    6767347
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    8111976
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    6866421
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:
CSF-1 in Dental Biology
CSF-1 在牙科生物学中的应用
  • 批准号:
    7882575
  • 财政年份:
    2004
  • 资助金额:
    $ 30.65万
  • 项目类别:

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