Research for the role of calcium-sensing receptor in parathyroid gland and bone

甲状旁腺和骨中钙敏感受体的作用研究

• 批准号: 12671087
• 负责人: SUGIMOTO Toshitsugu
• 金额: $ 2.18万
• 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: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671087/
• 关键词: Calcium-sensing receptor; Parathyroid; Bone; Parathyroid hormone; Proliferation; Vitamin D receptor; Polymorphism; Hyperparathyroidism; 家族性低カルシウム尿性高カルシウム血症; 原発性副甲状腺機能亢進症; 続発性副甲状腺機能亢進症; 骨リモデリング

The down-regulation of both calcium-sensing receptor (CaSR) and vitamin D receptor (VDR) in parathyroid (PT) glands of secondary hyperparathyroidism (HPT) caused by chronic renal failure has been associated with parathyroid hormone (PTH) hypersecretion as well as PT hypergrowth. The present study was performed to clarify the predominance of decreased CaSr and VDR in the high proliferative activity of PT glands. We obtained evidence that the decrease in CaSR expression is associated with the high proliferative activity of PT glands in secondary HPT, independently of the decreased VDR. Similar relationship was also observed in primary HPT. We also reported two cases of familial hypocalciuric hypercalcemia whose parathyroid glands were enlarged. Analysis of DNA sequence and receptor function revealed inactivated multations of CaSR (R220W, R648stop). Moreover, in primary culture of human parathyroid cells, high concentration of calcium as well as CaSR agonists inhibited PT proliferation. T … More he present findings indicate an important role of CaSR in the regulation of PT proliferation as well as PTH secretion. Primary and secondary HPT are heterogeneous diseases in the clinical course and severity. We raised the hypothesis that CaSR polymorphisms might be associated with the magnitude of PTH secretion and the clinical severity of primary and secondary HPT. In the present study, we analyzed the relationship between CaSR polymorphisms and biochemical markers. The present study is the first to show that CaSR polymorphisms in both codon 990 and intron 4 were closely associated with themagnitude of PTH secretion and thus the clinical severity in primary and secondary HPT patients. These polymorphisms would partly exsplain the heterogeneity of pathological severity in these diseases. As for bone, we demonstrated that both p42/44 and p38 MAP kinase cascades play pivotal roles in CaSR-stimulated mitogenic responses. Moreover, we also obtained data indicating a functional role of CaSR in the regulation of osteoblast function. Less

慢性肾功能衰竭继发性甲状旁腺功能亢进（HPT）患者的甲状旁腺钙敏感受体（CaSR）和维生素D受体（VDR）表达下调与甲状旁腺激素（PTH）分泌过多以及PT过度生长有关。本研究旨在阐明PT腺体高增殖活性中CaSr和VDR降低的优势。我们获得的证据表明，CaSR表达的减少与继发性HPT中PT腺体的高增殖活性相关，而与VDR的降低无关。在原发性HPT中也观察到类似的关系。我们也报告了两个家族性低尿钙高钙血症的病例，其甲状旁腺肿大。DNA序列分析和受体功能分析显示CaSR的失活突变（R220 W，R648 stop）。此外，在人甲状旁腺细胞的原代培养中，高浓度的钙以及CaSR激动剂抑制PT增殖。不 ...更多信息 目前的研究结果表明，CaSR在调节PT增殖以及PTH分泌方面具有重要作用。原发性和继发性HPT在临床病程和严重程度上是异质性疾病。我们提出了这样的假设，即CaSR多态性可能与PTH分泌的幅度和原发性和继发性HPT的临床严重程度相关。本研究分析了CaSR基因多态性与生化指标的关系。本研究首次发现CaSR基因第990密码子和第4内含子多态性与原发性和继发性HPT患者的PTH分泌量及临床严重程度密切相关。这些多态性部分解释了这些疾病病理严重程度的异质性。至于骨，我们证明了p42/44和p38 MAP激酶级联在CaSR刺激的促有丝分裂反应中起关键作用。此外，我们还获得的数据表明，在成骨细胞功能的调节中的功能性作用的钙离子受体。少

项目成果

Nakaoka D: "Evaluation of changes in bone density and biochemical parameters after parathyroidectomy in primary hyperparathyroidism"Endocvine J. 47・3. 231-237 (2000)

Nakaoka D：“原发性甲状旁腺功能亢进症甲状旁腺切除术后骨密度和生化参数变化的评估”Endocvine J. 47・3（2000）。

Bastepe M, Pincus JE, Sugimito T, Tojo K, Kanatani M, Azuma Y, Kruse K, Rosenbloom AL, Koshiyama H, Juppner H: "Positional dissociation between the genetic mutation responsible for pseudohypoparathyroidism type lb and the associated methylation defect at

Basstepe M、Pincus JE、Sugimito T、Tojo K、Kanatani M、Azuma Y、Kruse K、Rosenbloom AL、Koshiyama H、Juppner H：“导致 lb 型假性甲状旁腺功能减退症的基因突变与相关甲基化缺陷之间的位置分离

Nakaoka D, Sugimoto T, Kobayashi T, Yamaguchi T, Kobayashi A, Chihara K.: "Prediction of bone mass change after parathyroidectomy in patients with primary hyperparathyroidism"J Clin Endocrinol Metab. 85. 19001-1907 (2000)

Nakaoka D、Sugimoto T、Kobayashi T、Yamaguchi T、Kobayashi A、Chihara K.：“原发性甲状旁腺功能亢进症患者甲状旁腺切除术后骨量变化的预测”J Clin Endocrinol Metab。

Kanzawa M, Sugimoto T, Kobayashi T, Kobayashi A, Chihara K: "Association of parathyroid hormone (PTH)/PTH-related peptide receptor gene polymorphism with the extent of bone mass reduction in primary hyperparathyroidism"Horm Metab Res. 32. 355-358 (2000)

Kanzawa M、Sugimoto T、Kobayashi T、Kobayashi A、Chihara K：“甲状旁腺激素（PTH）/PTH相关肽受体基因多态性与原发性甲状旁腺功能亢进症骨质减少程度的关联”Horm Metab Res。

Yano S: "Association of polymorphic alleles of the calcium-sensing receptor gene with parathyroid hormone secretion in hemodialysis patients"Nephron. 85. 317-323 (2000)

Yano S：“钙敏感受体基因的多态性等位基因与血液透析患者甲状旁腺激素分泌的关联”肾单位。