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
项目成果
期刊论文数量(0)
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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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