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
骨丢失和骨折是随着年龄增长而发病的主要原因。年龄相关骨的机制
疾病尚未被定义。我们的研究表明,CSF-1缺乏和Nox 4氧化酶增加,
在骨细胞中的表达是氧化应激的关键决定因素,其影响骨细胞存活/功能,
对骨骼重塑至关重要这项提案的长期目标是描绘出
通过CSF-1/氧化应激调节骨细胞稳态并鉴定治疗靶点以预防
随着年龄的增长骨质流失。CSF-1和CSF-1 R由骨细胞表达。CSF-1或
其同种型,可溶性和细胞表面CSF-1,调节骨细胞存活/功能,
探讨了随着年龄的增长,氧化应激导致骨细胞死亡和骨丢失。我们的研究结果表明
随着年龄的增长,骨细胞中CSF-1的表达下降。我们制造了CSF-1缺乏的小鼠,
(CSF-1 KO),其显示具有增加的骨折和包括凋亡的骨细胞缺陷的骨硬化症,
与NADPH氧化酶Nox 4表达/活性增加和Cx43表达减少相关。CSF-1
降低培养的骨细胞中NADPH氧化酶的活性,并且CSF-1 KO骨细胞显示升高的
与WT骨细胞相比,Nox 4和mTOR通路的激活,表明CSF-1保护了骨细胞的增殖。
氧化应激骨细胞中CSF-1条件性敲除(cKO)的DMP 1Cre-CSF-1cKO小鼠/晚期
成骨细胞还显示出增加的Nox 4、骨细胞缺陷、减少的破骨细胞和骨形成,
随着年龄的增长易导致骨质流失和骨折。我们假设:a)CSF-1的骨细胞cKO增加
Nox 4和氧化应激损伤骨细胞并加速骨缺损,B)Nox 4的缺失,
CSF-1cKO骨细胞降低氧化应激,恢复骨细胞功能/随年龄的骨重塑,c)
CSF-1cKO骨细胞中sCSF-1的表达促进骨细胞存活和适当的骨重建,
比csCSF-1在衰老过程中的作用更大。我们将测试这些假设在以下具体目标:1)
确定骨细胞中CSF-1cKO对衰老过程中骨表型和氧化还原状态的影响。WT和
将检查CSF-1cKO小鼠的骨表型,并评估骨细胞的凋亡、Nox 4
2)确定Nox 4在CSF-1cKO小鼠骨细胞中的作用,
CSF-1调节骨细胞存活的机制。为了分析CSF-1和
Nox 4,将产生具有CSF-1和Nox 4在骨细胞中的cKO的小鼠,并且通过
将在培养的骨细胞中分析CSF-1调节骨细胞存活的能力; 3)确定CSF-1调节骨细胞存活的能力。
CSF-1同种型在CSF-1cKO小鼠中挽救骨缺损。这将通过使用转基因
靶向CSF-1cKO小鼠骨细胞中sCSF-1或csCSF-1的方法。这些研究将提供新的
CSF-1控制骨细胞存活/功能的机制见解,并可能导致新的治疗方法
提高骨细胞活力的策略对骨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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