ENDOTHELIN-1 IN NORMAL AND PATHOLOGICAL BONE REMODELING

内皮素-1 在正常和病理性骨重建中的作用

基本信息

批准号：
7158602
负责人：
THERESA A GUISE
金额：
$ 28.92万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-01 至 2008-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7158602
关键词：
Attenuated Bone Development Bone Growth Bone Resorption Bone Resorption Inhibition Bone remodeling CCAAT-enhancer-binding protein-delta Cancer Patient Chronic Clinical Trials Congestive Heart Failure Coronary Arteriosclerosis Data Development Diabetic Nephropathy Disease Endothelin Endothelin A Receptor Endothelin-1 Epidermal Growth Factor Receptor Estrogens Female Goals Gonadal Steroid Hormones Growth Homeostasis In Vitro Innate Bone Remodeling Interleukin-6 Investigation Ischemia Lead Ligands Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Neoplasm to the Bone Molecular Mus Neoplasm Metastasis Osteoblasts Osteoclasts Osteogenesis Pathway interactions Phenotype Physiological Play Protein Overexpression Pulmonary Hypertension Receptor Signaling Research Personnel Role Scleroderma Signal Pathway Signal Transduction Site Testing Transforming Growth Factor beta Vascular Endothelial Growth Factors bisphosphonate bone bone cell bone loss cerebrovascular endothelin-3 receptor factor C in vivo paracrine receptor research study transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): Endothelin-1 (ET-1) can cause osteoblastic bone metastases, stimulating dysregulated new bone formation by activating the endothelin A receptor (ETAR) on the osteoblast. The role of ET-1 in normal bone development, growth and remodeling is unclear. Our preliminary data indicate that: 1) ET-I is a potent stimulator of osteoblast activity and new bone formation in vivo; 2) Tumor-produced ET-1 stimulates osteoblastic metastases via ETAR; 3) ETAR blockade has sex steroid-dependent effects on bone mass: most strikingly, ETAR blockade reduces bone mass in hypogonadal but increases bone mass in intact female mice. 4) ET-1 increases expression of bone active factors IL-6 and Cyr61 and decreases that of Dkkl in osteoblasts, while increasing expression of the transcription factors C/EBPdelta and TSC-22. ET-1 did not alter EGFR activation or VEGF. The following hypotheses will be tested: 1) ET-1 plays an important role in normal bone remodeling. 2) ET-1 mediates effects on osteoblasts by changing the secretion of paracrine regulators 1L-6, Dkk1 and potentially Cyr61. 3) ET-1 increases the osteoblast transcription factor C/EBP\delta that interacts with Runx2, and TGFbeta-regulated TSC-22. 4) ETAR blockade results in reduced osteoblastic bone formation and increased osteoclast activity and may accelerates the osteoclastic bone resorption and subsequent bone loss associated with sex steroid deficiency. 5) Estrogen suppresses ET-1 synthesis. In estrogen-deficient states, increased ET-1 maintains bone mass Three Specific Aims are proposed: Aim 1: Determine the role of ET-1 and ETAR in normal bone development, growth, and remodeling 1A. Determine bone phenotype of mice with ETAR-null osteoblasts 1B. Determine bone phenotype of mice with ET-l- overexpressing osteoblasts Aim 2: Determine the role of ET-1 and ETAR in bone remodeling in sex-steroid deficient states 2A. Determine interactions between sex steroids and ET-1 in osteoblastic new bone formation 2B. Determine effects of combined inhibition of resorption and ETAR signaling on bone mass 2C. Determine bone phenotype of hypogonadal mice with ETAR-null or ET-1 ++g osteoblasts Aim 3: Determine the molecular mechanisms of ET-1 effects on bone 3A. Determine if ET-1 mediates its effects on osteoblasts via secreted IL-6, Dkk1, or Cyr61 3B. Determine effects of ET-1 on osteoblast transcription factors C/EBPdelta and TSC-22 3C. Determine major signaling pathways activated by ET-1 in osteoblasts 3D. Assess the interactions of sex steroids with ET-1 in bone cells The physiological role of ET-1 and ETAR in normal bone homeostasis needs investigation. 1, ETAR blockade is in clinical trials for many disease states, but the consequences for bone are unknown. Cancer patients treated with chronic ETAR blockade may suffer increased bone loss, in addition to that caused by sex-steroid deficiency. We will define the mechanisms and determine if this effect can be attenuated by bisphosphonate treatment. 2, an understanding of ET-1 activation of ETAR in the osteoblast may lead to new anabolic therapies for low bone mass. The experiments proposed will use in vivo and in vitro approaches to test the role of ET-1 activation of osteoblast ETAR in bone growth and remodeling.

描述（由申请人提供）：内皮素-1（ET-1）可以引起成骨细胞转移，从而通过激活成骨细胞上的内皮素A受体（ETAR）来刺激失调的新骨形成。 ET-1在正常骨发育，生长和重塑中的作用尚不清楚。我们的初步数据表明：1）ET-I是体内成骨细胞活性和新骨形成的有效刺激剂； 2）产生肿瘤的ET-1通过ETAR刺激成骨细胞转移； 3）ETAR封锁对性类固醇对骨骼的影响：最引人注目的是，Etar封锁减少了性交中的骨骼质量，但会增加完整雌性小鼠的骨骼量。 4）ET-1增加了骨骼活性因子IL-6和CYR61的表达，并降低成骨细胞中DKKL的表达，同时增加转录因子C/EBPDELTA和TSC-22的表达。 ET-1不会改变EGFR激活或VEGF。将测试以下假设： 1）ET-1在正常骨重塑中起重要作用。 2）ET-1通过更改旁分泌调节剂1L-6，DKK1和潜在的CYR61的分泌来介导对成骨细胞的影响。 3）ET-1增加了与Runx2相互作用的成骨细胞转录因子C/EBP \ delta和TGFBETA调节的TSC-22。 4）ETAR封锁导致成骨细胞的形成减少并增加破骨细胞活性，并可能加速骨质碎片性骨吸收和随后与性类固醇缺乏相关的骨质流失。 5）雌激素抑制ET-1合成。在缺陷雌激素的状态中，ET-1保持骨骼质量提出了三个具体目标：目标1：确定ET-1和ETAR在正常骨发育，生长和重塑1a中的作用。用Etar-Null成骨细胞确定小鼠的骨表型 1B。用ET-L过表达的成骨细胞确定小鼠的骨表型 AIM 2：确定ET-1和ETAR在性类替代状态中骨骼重塑中的作用 2a。确定性类固醇与ET-1之间的相互作用在成骨细胞新骨形成中 2b。确定吸收和ETAR信号的联合抑制对骨骼质量的影响 2C。用ETAR-NULL或ET-1 ++ G成骨细胞确定性低肿瘤小鼠的骨表型目标3：确定ET-1对骨骼的影响的分子机制 3a。确定ET-1是否通过分泌的IL-6，DKK1或CYR61介导其对成骨细胞的影响 3b。确定ET-1对成骨细胞转录因子C/EBPDELTA和TSC-22的影响 3C。确定由ET-1激活成骨细胞中的主要信号通路 3D。评估性类固醇与骨细胞中ET-1的相互作用 ET-1和ETAR在正常骨稳态中的生理作用需要研究。 1，ETAR阻滞在许多疾病状态的临床试验中，但骨骼的后果尚不清楚。除了性甾体疾病缺乏引起的癌症患者外，接受慢性ETAR封锁治疗的癌症患者可能会增加骨质流失。我们将定义机制，并确定是否可以通过双膦酸盐处理能够减弱这种作用。 2，对ETAR在成骨细胞中的ET-1激活的理解可能会导致低骨量的新代谢疗法。提出的实验将在体内和体外方法中测试成骨细胞ETAR在骨生长和重塑中的ET-1激活的作用。