PTH resistance and marrow adipogenesis
PTH 抵抗和骨髓脂肪生成
基本信息
- 批准号:9401167
- 负责人:
- 金额:$ 57.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdipocytesAdipose tissueAgeAge-Related Bone LossAge-Related OsteoporosisAnimal ModelAntibodiesAreaBioenergeticsBiopsyBirthBone MarrowBone ResorptionBone remodelingCell Differentiation processCell SeparationCellsCharacteristicsDataDevelopmentDisease modelEndocytosisExhibitsFatty acid glycerol estersFemaleGTP-Binding Protein alpha Subunits, GsGene Expression ProfileGenesGeneticGenetic ModelsGlycolysisGoalsHistologicHistologyImpairmentIn VitroIndividualKnockout MiceLeadLightMarrowMediatingMediator of activation proteinMesenchymalMesenchymal DifferentiationMesenchymal Stem CellsMessenger RNAMusMutant Strains MiceObesityOsmiumOsteoblastsOsteocytesOsteogenesisOsteoporosisOxidative PhosphorylationPPAR gammaPTH genePathway interactionsPeptidesPeripheralPhenotypePopulationProductionProteinsRecruitment ActivityRoleSerumSignal TransductionSignaling ProteinSkeletal boneSkeletonSmall Interfering RNASorting - Cell MovementStem cellsStromal CellsSumTNFSF11 geneTechniquesTechnologyTestingTomatoesWorkZinc Fingersadiponectinbonebone masscortical bonedriving forceexperimental studyhormone resistancein vivolipid biosynthesismalemenmicroCTmouse modelmutantnew technologynovelosteogenicosteoprogenitor cellparathyroid hormone (1-34)parathyroid hormone-related proteinprogenitorrecombinaserosiglitazoneskeletaltranscription factor
项目摘要
Age-related osteoporosis is characterized by enhanced skeletal fragility, low bone mass, secondary increases
in PTH, high bone resorption and marrow adiposity. Previous animal models for this disorder did not
recapitulate all these features. However, we developed a mouse model of impaired PTH function that develops
age-related bone loss relatively soon after birth. For example, we found that conditional deletion of the PTH1R
using the Prx1Cre recombinase led to a substantial increase in marrow adipose tissue (MAT) by 3 weeks of
age. This was accompanied by increased bone resorption, low bone mass and high RANKL expression in the
bone marrow and serum, even in the absence of functional PTH activity, and no change in osteocyte
number/area or lacunar area. Also we noted that PTH administration to the PTH1Rfl/fl control mice reduced
MAT volume by 50% but did not change MAT in the mutant mice. Similar findings were noted in men treated
with PTH for osteoporosis. To further delineate the origin of RANKL, we then isolated bone marrow adipocytes
from the Prx1cre;PTH1Rfl/fl mice and their controls, and found consistently high expression of adipose-related
genes; e.g., Pparγ, Cebp α,β,Δ, Fabp4 and Adiponectin as well as Rankl. Supernatant from spun marrow
showed an increase in RANKL protein (p<0.03) in the Prx1cre;PTH1Rfl/fl mutant mice. Progenitor cells removed
from the bottom layer of spun marrow in the mutant mice showed enhanced adipogenic differentiation,
increased RANKL expression, and co-localization of adiponectin and tomato red in the MSCs. Further, we
noted that Rankl mRNA was undetectable in any adipose depot outside the marrow. We also found that zinc
finger protein 467 (Zfp467), an early mesenchymal transcription factor that up-regulates Rankl, but is down
regulated by PTH, was 8 fold higher in mutant adipocytes, whereas treatment with PTH suppressed Zfp467
mRNA by 70% in cortical bone of controls but not in mutants. In this proposal we hypothesize that PTH
regulates marrow adipogenesis through suppression of Zfp467 and that the marrow adipocytes induced by
loss of PTH signaling are unique, arising from a mesenchymal progenitor, which expresses both adipogenic
and osteogenic markers.
We propose two specific aims to test this hypothesis: 1) Determine the role of PTH1R in cell fate decisions of
mesenchymal progenitor cells using genetic mouse models, define the downstream mediator of PTH1R in
regulating bone marrow adipogenesis, and perform bioenergetic analyses; 2) Determine whether bone marrow
adipocytes are the driving force via RANKL to enhance bone resorption in the absence of PTH1R signaling
exploiting new technology for: 1-lineage tracing, 2-sorting marrow adipocytes, 3-treating with OPG and 4-
generating a novel mouse model. The results of these experiments could lead to new targets for treating
osteoporosis.
老年性骨质疏松症的特征是骨骼脆性增强,骨量减少,继发性增加
甲状旁腺功能亢进表现为高骨吸收和骨髓肥厚。之前针对这种疾病的动物模型并没有
概括一下所有这些特点。然而,我们开发了一种甲状旁腺素功能受损的小鼠模型
与年龄相关的骨丢失在出生后相对较快。例如,我们发现PTH1R的条件删除
使用Prx1Cre重组酶导致骨髓脂肪组织(MAT)在3周内显著增加
年龄。伴随着骨吸收增加、骨量减少和RANKL的高表达。
骨髓和血清,即使在没有功能性甲状旁腺素活性的情况下,骨细胞也没有变化
数量/面积或缺陷区。我们还注意到,PTH1Rfl/fl对照组小鼠的甲状旁腺素注射减少
MAT体积增加了50%,但突变小鼠的MAT没有改变。在接受治疗的男性中也发现了类似的发现。
甲状旁腺素治疗骨质疏松症。为了进一步阐明RANKL的来源,我们分离了骨髓脂肪细胞。
从Prx1cre;PTH1Rfl/fl小鼠及其对照组中发现,脂肪相关基因的持续高表达
基因,如PPARγ、CEBPα,β,Δ、FABP4和脂联素以及RANKL。纺丝骨髓上清液
在Prx1cre;PTH1Rfl/fl突变小鼠中,RANKL蛋白(p<;0.03)增加。祖细胞被移除
从突变小鼠的骨髓底层分离出的成脂分化增强,
RANKL表达增加,脂联素和番茄红在MSCs中共定位。此外,我们
注意到RANKL mRNA在骨髓外的任何脂肪储存库中都检测不到。我们还发现,锌
指蛋白467(Zfp467),一种早期间充质转录因子,上调RANKL,但下调
在突变的脂肪细胞中,受甲状旁腺素调节的Zfp467的表达增加了8倍,而甲状旁腺素处理则抑制了Zfp467
对照组皮质骨中的mRNA表达增加70%,而突变体中未见表达。在本提案中,我们假设Pth
抑制Zfp467调控骨髓脂肪生成及其诱导的骨髓脂肪细胞
甲状旁腺素信号的丢失是独一无二的,由间充质祖细胞引起,它表达成脂
和成骨标志物。
我们提出了两个具体的目标来检验这一假说:1)确定PTH1R在细胞命运决定中的作用
使用遗传小鼠模型的间充质祖细胞,定义PTH1R的下游介导物
调节骨髓脂肪生成,并进行生物能量分析;2)确定骨髓是否
脂肪细胞是在没有PTH1R信号的情况下通过RANKL促进骨吸收的驱动力
开发新技术:1-谱系追踪,2-分选骨髓脂肪细胞,3-OPG治疗和4-OPG治疗
生成一种新颖的小鼠模型。这些实验的结果可能导致治疗的新靶点。
骨质疏松。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ROLAND E BARON其他文献
ROLAND E BARON的其他文献
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{{ truncateString('ROLAND E BARON', 18)}}的其他基金
The role of the osteocyte in responses to osteoporosis anabolic treatment in humans and mice
骨细胞在人类和小鼠骨质疏松合成代谢治疗反应中的作用
- 批准号:
10404416 - 财政年份:2023
- 资助金额:
$ 57.66万 - 项目类别:
Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat
PTH的作用机制:调节骨形成和骨髓脂肪的新信号成分
- 批准号:
10598064 - 财政年份:2020
- 资助金额:
$ 57.66万 - 项目类别:
Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat
PTH的作用机制:调节骨形成和骨髓脂肪的新信号成分
- 批准号:
10370393 - 财政年份:2020
- 资助金额:
$ 57.66万 - 项目类别:
The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture
GGPS1和CYP1A1突变在非典型股骨骨折中的作用
- 批准号:
10055985 - 财政年份:2020
- 资助金额:
$ 57.66万 - 项目类别:
Mechanism of action of PTH: New signaling components that regulate bone formation and bone marrow fat
PTH的作用机制:调节骨形成和骨髓脂肪的新信号成分
- 批准号:
10159214 - 财政年份:2020
- 资助金额:
$ 57.66万 - 项目类别:
The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture
GGPS1和CYP1A1突变在非典型股骨骨折中的作用
- 批准号:
10222572 - 财政年份:2020
- 资助金额:
$ 57.66万 - 项目类别:
R-Spondin3 as a target for anabolic bone therapy
R-Spondin3 作为骨合成代谢治疗的靶点
- 批准号:
9478548 - 财政年份:2014
- 资助金额:
$ 57.66万 - 项目类别:
R-Spondin3 as a target for anabolic bone therapy
R-Spondin3 作为骨合成代谢治疗的靶点
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9250695 - 财政年份:2014
- 资助金额:
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R-Spondin3 as a target for anabolic bone therapy
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8693390 - 财政年份:2014
- 资助金额:
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