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Regulation and function of retinol binding protein in cartilage

软骨中视黄醇结合蛋白的调节和功能

基本信息

批准号：
11671842
负责人：
NOSHIRO Mitsuhide
金额：
$ 2.24万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671842/
关键词：
chondrocyte retinoic acid RBP PTH cAMP hedgehog

项目摘要

The following results were obtained to clarify the role of retinoic acid and PTH as the modulators in the growth and development of chondrocytes.(1) Parathyroid hormone (PTH) and dibutyryl cAMP ((Bu) 2cAMP) induced the expression of plasma retinol-binding protein (RBP) in the conditioned media of rabbit growth plate chondrocyte cultures.(2) Northern blot analysis showed that PTH, parathyroid hormone-related peptide (PTHrP) and (Bu) 2cAMP increased the RBP mRNA level in chondrocyte cultures. Further, both PTH and (Bu) 2cAMP markedly induced the expression of RBP mRNA indicating a pretranslational regulation. The level of the mRNA expression induced by PTH, PTHrP and (Bu) 2cAMP was as high as that by retinoic acid (RA).(3) Both RBP and PTH/PTHrP inhibited the dedifferentiative activity of RA on growth plate chondrocytes. These results demonstrate that chondrocytes synthesize and secrete RBP in vivo and in vitro, and suggest that PTH/PTHrP naodulates the effect of RA by means of RBP production in chondrocytes.(4) RA and bone morphogenetic protein-2 (BMP-2) enhanced Indian hedgehog (Ihh) mRNA expression, whereas PTH/PTH-related peptide (PTHrP) markedly suppressed Ihh expression.(5) Cycloheximide blocked the up-regulation of Ihh by RA, indicating the requirement of de novo protein synthesis for this stimulation. These findings suggest that RA is involved in the up-regulation of Ihh during endochondral bone formation.(6) PTH rapidly abolished the mRNA expression of Ihh. The inhibition of Ihh expression by PTH (1-84) did not require de novo protein synthesis. The direct inhibitory action of PTH/PTHrP on Ihh appears to be a negative feedback mechanism that prevents excess PTHrP accumulation in cartilage.

为了阐明视黄酸和甲状旁腺激素作为调节剂在软骨细胞生长发育中的作用，我们获得了以下结果。(1)甲状旁腺激素（PTH）和二丁基cAMP （(Bu) 2cAMP）诱导兔生长板软骨细胞培养条件培养基中血浆视黄醇结合蛋白（RBP）的表达。(2) Northern blot分析显示，PTH、甲状旁腺激素相关肽（PTHrP）和（Bu） 2cAMP可提高软骨细胞培养RBP mRNA水平。此外，PTH和（Bu） 2cAMP均能显著诱导RBP mRNA的表达，表明其具有翻译前调控作用。PTH、PTHrP和（Bu） 2cAMP诱导的mRNA表达水平与维甲酸（RA）诱导的mRNA表达水平相当。(3) RBP和PTH/PTHrP均能抑制RA对生长板软骨细胞的去分化活性。这些结果表明，体内和体外软骨细胞均能合成和分泌RBP，提示PTH/PTHrP通过软骨细胞生成RBP调节RA的作用。(4) RA和骨形态发生蛋白-2 （BMP-2）增强了印度刺猬（Ihh） mRNA的表达，而PTH/PTH相关肽（PTHrP）显著抑制了Ihh的表达。(5)环己亚胺阻断了RA对Ihh的上调，表明这种刺激需要从头合成蛋白质。这些发现表明RA参与了软骨内骨形成过程中Ihh的上调。(6) PTH迅速消除Ihh mRNA的表达。PTH对Ihh表达的抑制（1-84）不需要从头合成蛋白质。PTH/PTHrP对Ihh的直接抑制作用似乎是一种防止软骨中过量PTHrP积聚的负反馈机制。