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
- 批准号:8631392
- 负责人:
- 金额:$ 30.65万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-09-30 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingAlbers-Schonberg diseaseApoptosisBiologyBone DiseasesBone remodelingBreedingCell surfaceConnexin 43ConnexinsDataDefectDominant-Negative MutationEnzyme-Linked Immunosorbent AssayFractureGap JunctionsGene ExpressionGene Expression ProfileGenesGeneticGoalsHealthHistologyHomeostasisIn Situ HybridizationKnock-outLeadLongevityMacrophage Colony-Stimulating FactorMechanicsMitochondriaModelingMorbidity - disease rateMusNADPH OxidaseOsteoblastsOsteoclastsOsteocytesOsteogenesisOxidasesOxidation-ReductionOxidative StressPathway interactionsPatternPhenotypeProtein IsoformsRelative (related person)Reverse Transcriptase Polymerase Chain ReactionRoleSignal TransductionSmall Interfering RNATNFSF11 geneTestingTherapeuticTransgenic OrganismsWorkactivity markerage relatedbonebone lossbone massbone strengthbone turnoverhuman FRAP1 proteinimprovedinsightinterestlaser capture microdissectionnew therapeutic targetnovelnovel therapeuticsoverexpressionoxidant stresspreventpublic health relevancereceptorskeletaltherapeutic target
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:
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