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

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.
骨质疏松症的特点是骨骼脆性增强,骨量降低,继发性增加, PTH、高骨吸收和骨髓肥胖。以前这种疾病的动物模型没有 概括了所有这些特征。然而,我们开发了一种PTH功能受损的小鼠模型, 与年龄相关的骨质流失相对出生后不久。例如,我们发现PTH1R的条件性缺失 使用Prx1Cre重组酶导致骨髓脂肪组织(MAT)在3周内显著增加, 年龄这伴随着骨吸收增加,低骨量和高RANKL表达, 骨髓和血清,即使在没有功能性PTH活性的情况下,骨细胞也没有变化, 数量/面积或腔隙面积。我们还注意到,对PTH 1Rfl/fl对照小鼠的PTH给药降低了 MAT体积减少50%,但在突变小鼠中没有改变MAT。在接受治疗的男性中也观察到类似的发现 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,发现脂肪相关的 基因;例如,Ppar γ、Cebp α、β、Δ、Fabp4和脂联素以及Rankl。离心骨髓上清液 在Prx1cre; PTH1Rfl/fl突变小鼠中显示RANKL蛋白增加(p <0.03)。去除祖细胞 从突变小鼠的离心骨髓底层中提取的DNA显示出增强的脂肪形成分化, RANKL表达增加,脂联素和番茄红在MSC中共定位。我们还 注意到Rankl mRNA在骨髓外的任何脂肪储库中都检测不到。我们还发现锌 指蛋白467(Zfp467),一种上调Rankl但下调Rankl的早期间充质转录因子, 在突变型脂肪细胞中,由PTH调节的Zfp467是正常的8倍,而用PTH处理抑制Zfp467 mRNA的70%,在皮质骨的控制,但不是在突变体。在本提案中,我们假设PTH 通过抑制Zfp467调节骨髓脂肪生成, 甲状旁腺素信号传导的损失是独特的,由间充质祖细胞引起,其表达成脂细胞和成纤维细胞。 和成骨标志物。 我们提出了两个具体的目标来验证这一假设:1)确定PTH1R在细胞命运决定中的作用, 间充质祖细胞,使用遗传小鼠模型,定义下游介质的PTH1R, 调节骨髓脂肪生成,并进行生物能量分析; 2)确定骨髓 脂肪细胞是通过RANKL的驱动力,在没有PTH1R信号传导的情况下增强骨吸收 开发新技术:1-谱系追踪,2-分选骨髓脂肪细胞,3-OPG处理和4- 产生新的小鼠模型。这些实验的结果可能会导致新的治疗目标 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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ROLAND E BARON其他文献

ROLAND E BARON的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
PTH resistance and marrow adipogenesis
PTH 抵抗和骨髓脂肪生成
  • 批准号:
    9979845
  • 财政年份:
    2017
  • 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
  • 批准号:
    9250695
  • 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
  • 批准号:
    8693390
  • 财政年份:
    2014
  • 资助金额:
    $ 57.66万
  • 项目类别:

相似海外基金

Examination of factors associated with trunk intramuscular adipose tissue content : Aspects of sex, age, and racial differences
躯干肌内脂肪组织含量相关因素的检查:性别、年龄和种族差异
  • 批准号:
    23KJ1130
  • 财政年份:
    2023
  • 资助金额:
    $ 57.66万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Does age-dependent PFKFB3 down-regulation alter adipose tissue function
年龄依赖性 PFKFB3 下调是否会改变脂肪组织功能
  • 批准号:
    10563615
  • 财政年份:
    2022
  • 资助金额:
    $ 57.66万
  • 项目类别:
Dietary Protein Restriction Remodels Adipose Tissue to Defend Against Age-Related Metabolic Decline
饮食蛋白质限制重塑脂肪组织以防御与年龄相关的代谢下降
  • 批准号:
    10828031
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:
Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment
针对年龄相关血管认知障碍的脂肪组织生热作用
  • 批准号:
    10490299
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:
Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment
针对年龄相关血管认知障碍的脂肪组织生热作用
  • 批准号:
    10674854
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:
Dietary Protein Restriction Remodels Adipose Tissue to Defend Against Age-Related Metabolic Decline
饮食蛋白质限制重塑脂肪组织以防御与年龄相关的代谢下降
  • 批准号:
    10302155
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:
Dietary Protein Restriction Remodels Adipose Tissue to Defend Against Age-Related Metabolic Decline
饮食蛋白质限制重塑脂肪组织以防御与年龄相关的代谢下降
  • 批准号:
    10478936
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:
Targeting adipose tissue thermogenesis for age-related vascular cognitive impairment
针对年龄相关血管认知障碍的脂肪组织生热作用
  • 批准号:
    10283749
  • 财政年份:
    2021
  • 资助金额:
    $ 57.66万
  • 项目类别:
Analysis of physiological roles of FABP5 in age-related chronic inflammation in adipose tissue
FABP5在脂肪组织年龄相关慢性炎症中的生理作用分析
  • 批准号:
    19K20172
  • 财政年份:
    2019
  • 资助金额:
    $ 57.66万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The pathological role of brown adipose tissue dysfunction in age related disorders.
棕色脂肪组织功能障碍在年龄相关疾病中的病理作用。
  • 批准号:
    26893080
  • 财政年份:
    2014
  • 资助金额:
    $ 57.66万
  • 项目类别:
    Grant-in-Aid for Research Activity Start-up
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了