Regulation of Osteoblasts by ACTH and VEGF
ACTH 和 VEGF 对成骨细胞的调节
基本信息
- 批准号:10001755
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-10-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetatesAdrenal Cortex HormonesAdrenal GlandsAnimal ModelBlood VesselsBlood capillariesBone GrowthBone necrosisCell Culture TechniquesCell HypoxiaCell ProliferationCellsCessation of lifeCircadian RhythmsClinicalComplexCorticotropinCorticotropin ReceptorsDependenceDifferentiation and GrowthDoseEndothelial Growth Factors ReceptorFeedbackFrequenciesGlucocorticoidsHeadHormonesHourHumanHypoxiaImmuneIn VitroInflammatoryInjectionsLightLymphocyteMeasuresMediatingMesenchymal Stem CellsMetabolicMethodsMethylprednisoloneModelingMusOryctolagus cuniculusOsteoblastsPF4 GenePituitary GlandProductionRegulationRegulatory PathwaySerumSignal TransductionSteroidsSystemT-LymphocyteTimeTissuesVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsWorkautocrinebonebone cellbone massbone turnovercytokinehuman diseasehuman modelin vivoinnovationmacrophagenovelpreventresponsesubstantia spongiosatissue culture
项目摘要
We are studying how osteoblast death due to glucocorticoids (GCs) is counteracted by vascular
endothelial growth factor (VEGF). Developing osteoblasts express the ACTH receptor, and osteoblasts
express VEGF in response to the adrenocorticotropic hormone (ACTH). Continuous steroid treatment reduces
ACTH production to low levels. In rabbits with high-dose GC, we showed that intermittent ACTH at minimum
doses to elevate ACTH for four hours greatly reduced osteonecrosis. Our recent studies show that osteoblast
growth and differentiation is increased by VEGF. Further, ACTH is one of several factors that regulate VEGF
production in bone. Thus, in bone, as in the adrenal, the actions of ACTH are complex, and systematic work
will be needed to determine how ACTH, VEGF, and other regulatory pathways interact in bone.
Our hypothesis is that ACTH is a major regulator of bone growth and survival in regions with rapid bone
turnover such as femoral head trabecular bone. The work planned will find quantitative ACTH doses,
currently unknown, that increase bone mass. Work planned we will use a rabbit animal model, and human
cells to assure relevancy to human disease. Our work using mice encountered difficulties in modeling human
bone response; at present the best animal model for osteonecrosis is the rabbit.
Gaps in understanding include downstream actions of ACTH in bone cells. Interactions of ACTH with
other systems that regulate VEGF, mediated by inflammatory cells, hypoxia, and by additional cytokines. It is
not known how response of bone in vivo varies with the dose or interval of ACTH administration.
Specific Aim 1 will use methylprednisolone acetate (MPA)-treated rabbits to define the dependency of
osteonecrosis on VEGF synthesis, ACTH concentration, and dose interval. Specifically, we will define
concentration dependency of ACTH effects. We will study effects on VEGF production of varying ACTH
injection, relative to depot MPA alone or in untreated rabbits. ACTH will be injected daily, at 8 AM, at 0.01,
0.03, 0.1, and 0.3 µg/kg, for 28 days. Osteonecrosis, bone turnover, serum ACTH and corticosteroids will be
measured. This will establish the relationship of specific ACTH doses to suppression of osteonecrosis.
Additionally, to define effect of frequency of ACTH administration on efficacy, we will compare the effects of
ACTH at 0.05 or 0.15 µg/kg twice daily versus 0.1 or 0.3 µg/kg once daily.
Specific Aim 2 will study the mechanism of response of human osteoblasts to ACTH and VEGF in vitro.
To determine whether ACTH provides survival signals in addition to VEGF, we will study the response of
osteoblasts to VEGF, with and without ACTH. Cell proliferation and matrix synthesis will be measured, as well
as production of regulatory cytokines by osteoblasts under normal and hypoxic conditions. Further to define the
VEGF response, we will make osteoblasts with VEGF receptors -1 and -2 (flt-1 and flk-1) eliminated. This will
allow ACTH effects to be defined in the absence of autocrine VEGF response.
Specific Aim 3 will determine how ACTH modulates VEGF production in glucocorticoid-treated human
cells. This will include evaluating the extent to which immune cells regulate production of VEGF by osteoblasts.
To do this, we will make mixed cultures including macrophages or T-lymphocytes. We will characterize VEGF
production in these cultures, and determine whether VEGF regulation involves specific cytokines, and its
sensitivity to glucocorticoids. In addition, we will determine whether ACTH synthesis occurs in bone in
meaningful amounts. Specifically, we will analyze pro-opiomelanocorticoid (POMC) expression and processing
in bone cells including osteoblasts, lymphocytes and macrophages.
This work will define a new metabolic regulatory pathway in bone, using innovative methods. It will shed
new light on mechanisms that contribute to osteonecrosis, which is a serious and common problem.
我们正在研究血管如何抵消糖皮质激素(GCs)引起的成骨细胞死亡
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Harry C. Blair其他文献
Osteoclastic differentiation and function regulated by old and new pathways
- DOI:
10.1007/s11154-006-9010-4 - 发表时间:
2006-06-01 - 期刊:
- 影响因子:8.000
- 作者:
Harry C. Blair;Mone Zaidi - 通讯作者:
Mone Zaidi
Plus ça change . . .
加一个改变。
- DOI:
10.1017/s0017257x00018698 - 发表时间:
1972 - 期刊:
- 影响因子:2.8
- 作者:
Edward Feit;Paul H. Lewis;Harry C. Blair - 通讯作者:
Harry C. Blair
Beyond Reproduction: Pituitary Hormone Actions on Bone.
超越生殖:垂体激素对骨骼的作用。
- DOI:
10.1016/bs.pmbts.2016.08.004 - 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
T. Yuen;Li Sun;Peng Liu;Harry C. Blair;M. New;A. Zallone;Mone Zaidi - 通讯作者:
Mone Zaidi
Regulation of Avian Osteoclastic H+-ATPase and Bone Resorption by Tamoxifen and Calmodulin Antagonists
他莫昔芬和钙调蛋白拮抗剂对禽破骨细胞 H-ATP 酶和骨吸收的调节
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:4.8
- 作者:
John P. Williams;Harry C. Blair;M. McKenna;S. Jordan;Jay M. McDonald - 通讯作者:
Jay M. McDonald
Harry C. Blair的其他文献
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{{ truncateString('Harry C. Blair', 18)}}的其他基金
Epithelial Osteoblast Function: The Role of Acid Transport
上皮成骨细胞功能:酸转运的作用
- 批准号:
10335222 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Epithelial Osteoblast Function: The Role of Acid Transport
上皮成骨细胞功能:酸转运的作用
- 批准号:
10155434 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Epithelial Osteoblast Function: The Role of Acid Transport
上皮成骨细胞功能:酸转运的作用
- 批准号:
9978494 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Epithelial Osteoblast Function: The Role of Acid Transport
上皮成骨细胞功能:酸转运的作用
- 批准号:
10555277 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Epithelial Osteoblast Function: The Role of Acid Transport
上皮成骨细胞功能:酸转运的作用
- 批准号:
10001865 - 财政年份:2019
- 资助金额:
-- - 项目类别: