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Research for the mechanisms of anabolic action of parathyroid hormone (PTH) and interaction between PTH and estrogen

甲状旁腺激素（PTH）合成代谢作用机制及PTH与雌激素相互作用的研究

基本信息

批准号：
09671060
负责人：
SUGIMOTO Toshitsugu
金额：
$ 1.79万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

It is well known that parathyroid hormone (PTH) possesses catabolic as well as anabolic action in bone, but the mechanisms of its anabolic action remained unknown. The present study demonstrated that not only insulin-like growth factor (IGF)-I but also IGF-binding protein-5 (IGFBP-5) were involved in the anabolic action of PTH in bone. Although it has been generally accepted that the biological activity of the PTH molecule mainly exists in the amino-terminal region of this molecule, there have also been several lines of evidence that some biological activities exist in carboxyl-terminal fragment. The present study demonstrated that carboxyl-terminal portion of the PTH molecule exercised biological activities in mRNA expression of type-I procollagen as well as IGFBP-5 in osteoblasts and that these would be involved in the anabolic action of PTH in bone in vivo. Moreover, clinical studies obtained from changes in bone mass after parathyroidectomy in primary hyperparathyroidism demonstrat … More ed that rapid reduction in endogenous PTH concentration played a crucial role in the anabolic action of PTH in bone. On the other hand, several lines of evidence indicate that estrogen inhibits PTH-induced bone resorption in viva and invitro, but its precise mechanisms remained unclear. Our previous study demonstated estrogen inhibited PTH-induced osteoclast formation in unfractionated bone cells, but it remained still unclear what kind of cells in bone were responsible for this interaction between PTH and estrogen. The present study demonstrated that PTH receptors and estrogen receptors both existed in hemopoietic blast cells, that is, osteoclast precursor cells. Estrogen inhibited PTH- induced osteoclast formation by directly acting on hemopoietic blast cells and the inhibitory effects of estrogen on PTH-induced osteoclast formation were mediated through blocking cAMP-dependent protein kinase. The present study indicated that the enhanced PTH-induced osteoclastgenesis in the absence of estrogen was partly involved in the increase in osteoclast number associated with postmenopausal osteoporosis. Less

众所周知，甲状旁腺激素（PTH）在骨中具有分解代谢和合成代谢作用，但其合成代谢作用的机制仍不清楚。本研究表明，不仅胰岛素样生长因子（IGF）-I，而且IGF结合蛋白-5（IGFBP-5）也参与骨中PTH的合成代谢作用。虽然人们普遍认为PTH分子的生物活性主要存在于该分子的氨基末端区域，但也有一些证据表明一些生物活性存在于羧基末端片段中。本研究表明，PTH 分子的羧基末端部分在成骨细胞中 I 型前胶原和 IGFBP-5 的 mRNA 表达中发挥生物活性，并且这些将参与 PTH 在体内骨中的合成代谢作用。此外，从原发性甲状旁腺功能亢进症甲状旁腺切除术后骨量变化获得的临床研究表明，内源性 PTH 浓度的快速降低在骨中 PTH 的合成代谢作用中发挥着至关重要的作用。另一方面，多项证据表明雌激素在体内和体外抑制 PTH 诱导的骨吸收，但其确切机制仍不清楚。我们之前的研究表明，雌激素抑制普通骨细胞中 PTH 诱导的破骨细胞形成，但仍不清楚骨中哪种细胞负责 PTH 和雌激素之间的这种相互作用。本研究表明，PTH受体和雌激素受体均存在于造血母细胞，即破骨细胞前体细胞中。雌激素通过直接作用于造血母细胞来抑制PTH诱导的破骨细胞形成，并且雌激素对PTH诱导的破骨细胞形成的抑制作用是通过阻断cAMP依赖性蛋白激酶介导的。本研究表明，在缺乏雌激素的情况下，PTH 诱导的破骨细胞生成增强部分参与了与绝经后骨质疏松症相关的破骨细胞数量的增加。较少的