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Molecular Analysis of PTHrP Receptor in Chondrocytes

软骨细胞 PTHrP 受体的分子分析

基本信息

批准号：
07671599
负责人：
OHTSURU Akira
金额：
$ 1.47万
依托单位：
Nagasaki University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671599/
关键词：
chondrocyte PTHrP receptor PTHrP osteoarthritis rheumatic arthritis PTH 変形性膝関節症 chondrocyte cloning

项目摘要

To elucidate the physiology of parathyroid-hormone-related peptide (PTHrP) in chondrocytes, it is essential to investigate on the molecular mechanism of PTHrP receptor mediated signal transduction because PTHrP knock-out mice developed achondroplasia like deformity. In the present projects, we have concentrated in the receptor-mediated signal transduction and PTHrP expression of various cartilage disease. In the former, we have studied the effect of various fragments of PTHrP in primary culture of rat articular chondrocytes and function of the cell lines transfected PTHrP.In the later, we have analyzed the pathophysiological role of parathyroid-hormone-related peptide (PTHrP) in osteoarthritis and rheumatic arthritis.The action of exogenously added hPTHrP (1-34), hPTHrP (1-141), hPTHrP (100-114) and hPTH (1-34) on thymidine incorporation, alpha (1) type II collagen gene expression, intracellular cAMP and [Ca^<2+>] i level was similar. Antisense oligonucleotides decreased PTHrP mRNA tra … More nslation specifically inhibited DNA synthesis. These data are speculated that there is no significant difference among exogenously added hPTH and hPTHrP,on the other hand intracellular PTHrP may have a yet unknown biological role, in addition to a classical PTH/PTHrP receptor-mediated function (J Endocrinology 150 : 359-368 1996).In tissue regeneration of osteoarthritis and rheumatic arthritis, PTHrP is a key cytokine regulated the cell motility and apoptosis (Br J Rheumatol 35 : 1056-1062 1996, J Osteopaedic Res, in press). To further extend the basic research, we have focused on the critical events of chondrocytes induced by abnormal expression of cytokines escaping from physiological regeneration or apoptosis, which can eventually induce gene instability and abnormal cell proliferation. The experimental design is in vivo rat animal model which was implanted with PTHrP producing osteoblast like cell and developed bone matrix formation around the cells (Endocrine J 43 : 527-535 1996). Furthermore, we have applied the antisense PTHrP oligonucleotide therapy against PTHrP producing tumor (Cancer Res 56 : 77-86,1996).Finally, we acknowledge a support from this grant and a valuable contribution of our post doc fellows and staffs. Less

为了阐明甲状旁腺激素相关肽（PTHrP）在软骨细胞中的生理作用，研究PTHrP受体介导的信号转导的分子机制是必要的，因为PTHrP敲除小鼠会发生软骨发育不全样畸形。在目前的项目中，我们主要集中在各种软骨疾病的受体介导的信号转导和PTHrP的表达。在前者中，我们研究了PTHrP不同片段在大鼠关节软骨细胞原代培养中的作用以及转染PTHrP的细胞系的功能。在后者中，我们分析了甲状旁腺激素相关肽（PTHrP）在骨关节炎和风湿性关节炎中的病理生理作用。外源添加hPTHrP（1-34）、hPTHrP（1-141）、hPTHrP（100-114）和hPTH（1-34）对胸苷结合、α(1)型胶原基因表达、细胞内cAMP和[Ca^<2+>] i水平的影响相似。反义寡核苷酸减少PTHrP mRNA的传递，更多的是特异性抑制DNA合成。这些数据推测外源性添加的hPTH和hPTHrP之间没有显著差异，另一方面，细胞内的PTHrP除了具有经典的PTH/PTHrP受体介导的功能外，可能还有未知的生物学作用（J Endocrinology 150: 359-368 1996）。在骨关节炎和风湿性关节炎的组织再生中，PTHrP是调节细胞运动和凋亡的关键细胞因子（Br J Rheumatol 35: 1056-1062 1996, J Osteopaedic Res, In press）。为了进一步拓展基础研究，我们将重点关注细胞因子异常表达诱导软骨细胞脱离生理性再生或凋亡，最终导致基因不稳定和细胞异常增殖的关键事件。实验设计为体内大鼠动物模型，植入产生成骨细胞样细胞的PTHrP，细胞周围形成骨基质（内分泌杂志43:527-535 1996）。此外，我们还应用反义PTHrP寡核苷酸治疗PTHrP产生的肿瘤（Cancer Res 56: 77-86,1996）。最后，我们感谢这项资助的支持以及我们博士后研究员和工作人员的宝贵贡献。少