HIF-2alpha, a Novel Regulator of Osteoblastogenesis
HIF-2alpha,成骨细胞生成的新型调节剂
基本信息
- 批准号:10536669
- 负责人:
- 金额:$ 35.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-11 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAgeAgingBiologyBirthBone MarrowCalvariaCellsChronic DiseaseClinical TrialsConventional (Clear Cell) Renal Cell CarcinomaDataDevelopmentEnvironmentGeneticHypoxiaHypoxia Inducible FactorImpairmentIn VitroKnowledgeLimb BudMediatingMediatorMesenchymal Stem CellsMusMutant Strains MiceMutationNewborn InfantOsteoblastsOsteogenesisOsteoporosisOxygenPathogenesisPathologyPatientsPeriosteal CellPhenotypeReportingRoleSignal PathwaySkeletal DevelopmentSkeletonStromal CellsTherapeuticTransgenic Micebonebone masscell typecortical bonegain of function mutationin vivoloss of functionloss of function mutationmutantnormoxianovelnovel therapeutic interventionosteoblast differentiationosteoprogenitor cellpostnatalprenatalresponseskeletal disordersmall moleculesubstantia spongiosatranscription factor
项目摘要
ABSTRACT
Advancing our understanding of the mechanisms that control bone mass and osteoblast differentiation is crucial
to unveil the pathogenesis of skeletal diseases and identify therapeutical approaches for their treatment.
Osteoblastic cells operate in a low oxygen (hypoxic) environment. The transcription factors Hypoxia Inducible
Factor-1a (HIF1) and HIF2 are critical mediators of the cellular response to hypoxia. Both transcription factors
are expressed in cells of the osteoblast lineage. HIF1 was reported to be a positive regulator of bone formation
and osteoblast differentiation. Conversely, the role of HIF2 in the control of bone mass and osteoblast biology is
still poorly understood. We recently generated mutant mice carrying loss-of-function and gain-of-function
mutations of HIF2 in mesenchymal progenitors of the limb bud by using PRX1-Cre. Preliminary analysis of these
mutant mice suggested that HIF2 is a negative regulator of osteoblastogenesis and bone formation through a
direct action on cells on the osteoblast lineage. Mechanistically, we gathered preliminary evidence that Sox9,
which is emerging as a negative regulator of osteoblast differentiation, is likely to mediate the HIF2-dependent
impairment of osteoblastogenesis. Our findings constitute a paradigm shift as activation of the HIF signaling
pathway has been associated with increased, rather than decreased, osteoblast activity. Moreover, they imply
that, as in other cell types, HIF1 and HIF2 have opposing functions in osteoblastic cells. Also, our preliminary
data showed that loss of HIF2 in mesenchymal progenitors of the limb bud increases bone mass in both
trabecular and cortical bone. HIF2 can be selectively inhibited by small molecules, some of which are currently
in clinical trials in patients carrying pathologies associated with high levels of HIF2 activity such as clear cell
renal carcinoma. Therefore, determining whether and how HIF2 controls osteoblastogenesis and bone mass
not only will expand and deepen our understanding of the role of the hypoxia signaling pathway in the skeleton
but could also provide a novel target for the treatment of low bone mass seen in chronic diseases, osteoporosis
and with aging. In this proposal, we thus seek to demonstrate that osteoblastic HIF2 regulates bone mass during
skeletal development and in adulthood (Aim 1). Moreover, we will establish whether osteoblastic HIF2 controls
osteoblastogenesis through a direct action on mesenchymal progenitors and in a Sox9-dependent manner (Aim
2).
!
摘要
提高我们对控制骨量和成骨细胞分化的机制的理解是至关重要的。
揭示骨骼疾病的发病机制,并找出治疗方法。
成骨细胞在低氧(低氧)环境中工作。低氧诱导的转录因子
因子-1a(HIF1)和HIF2是细胞对低氧反应的关键介质。两种转录因子
在成骨细胞系的细胞中表达。据报道,HIF1是骨形成的积极调节因子。
和成骨细胞分化。相反,HIF2在骨量控制和成骨细胞生物学中的作用是
人们对此仍知之甚少。我们最近培育出了携带功能丧失和功能获得的突变小鼠
应用PRX1-CRE技术检测肢芽间充质祖细胞中HIF2的突变对这些问题的初步分析
突变小鼠提示,HIF2是成骨细胞形成和骨形成的负调控因子,通过
直接作用于成骨细胞谱系上的细胞。从机制上讲,我们收集到的初步证据表明,
它正在成为成骨细胞分化的负调控因子,可能介导HIF2依赖的
成骨细胞生成障碍。我们的发现构成了一种范式转变,即HIF信号的激活
途径与成骨细胞活性增加有关,而不是减少。此外,它们还暗示
与其他类型的细胞一样,HIF1和HIF2在成骨细胞中具有相反的功能。另外,我们的初选
数据显示,肢芽间充质祖细胞中HIF2的缺失增加了两边的骨量
骨小梁和皮质骨。HIF2可以被小分子选择性地抑制,其中一些目前
在携带与高水平HIF2活性相关的病理的患者的临床试验中,如透明细胞
肾癌。因此,确定HIF2是否以及如何控制成骨细胞生成和骨量
不仅将扩大和加深我们对缺氧信号通路在骨骼中的作用的理解
但也可以为治疗慢性疾病如骨质疏松症中出现的低骨量提供一个新的靶点
随着年龄的增长。因此,在这个建议中,我们试图证明成骨细胞HIF2在
骨骼发育和成年期(目标1)。此外,我们将确定成骨细胞HIF2是否控制
通过直接作用于间充质祖细胞并以Sox9依赖的方式形成成骨细胞(目的
2)。
好了!
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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Ernestina Schipani其他文献
Ernestina Schipani的其他文献
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{{ truncateString('Ernestina Schipani', 18)}}的其他基金
Hypoxia and mitochondria in spine development and congenital scoliosis
脊柱发育和先天性脊柱侧弯中的缺氧和线粒体
- 批准号:
10640491 - 财政年份:2023
- 资助金额:
$ 35.75万 - 项目类别:
2022 Bones and Teeth Gordon Research Conference and Seminar
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10376959 - 财政年份:2021
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$ 35.75万 - 项目类别:
Regenerating Hyaline Cartilage Using Nanofibrous Hollow Microspheres and Synergizing TGF-beta and HIF
使用纳米纤维空心微球并协同 TGF-β 和 HIF 再生透明软骨
- 批准号:
10337864 - 财政年份:2020
- 资助金额:
$ 35.75万 - 项目类别:
Mitochondria and TFAM in Osteoblast Biology
成骨细胞生物学中的线粒体和 TFAM
- 批准号:
10531537 - 财政年份:2019
- 资助金额:
$ 35.75万 - 项目类别:
HIF-2alpha, a Novel Regulator of Osteoblastogenesis
HIF-2alpha,成骨细胞生成的新型调节剂
- 批准号:
10320694 - 财政年份:2019
- 资助金额:
$ 35.75万 - 项目类别:
HIF-2alpha, a Novel Regulator of Osteoblastogenesis
HIF-2alpha,成骨细胞生成的新型调节剂
- 批准号:
10391569 - 财政年份:2019
- 资助金额:
$ 35.75万 - 项目类别:
Mitochondria and TFAM in Osteoblast Biology
成骨细胞生物学中的线粒体和 TFAM
- 批准号:
9977917 - 财政年份:2019
- 资助金额:
$ 35.75万 - 项目类别:
Mitochondria and TFAM in Osteoblast Biology
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