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

慢性肾功能衰竭引起的继发性甲状旁腺功能亢进（HPT）患者甲状旁腺钙敏感受体（CaSR）和维生素D受体（VDR）下调与甲状旁腺激素（PTH）高分泌和PT过度生长有关。本研究旨在阐明在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表达的降低与继发性HPT中PT腺体的高增殖活性有关，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2例家族性低钙性高钙血症，其甲状旁腺肿大。DNA序列和受体功能分析显示CaSR （R220W, R648stop）发生失活突变。此外，在人甲状旁腺细胞原代培养中，高浓度的钙和CaSR激动剂抑制了PT的增殖。此外，目前的研究结果表明，CaSR在调节PT增殖和PTH分泌中起重要作用。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CaSR多态性可能与PTH分泌量和原发性和继发性HPT的临床严重程度有关的假设。在本研究中，我们分析了CaSR多态性与生化标志物之间的关系。本研究首次表明，密码子990和内含子4的CaSR多态性与原发性和继发性HPT患者PTH分泌的大小以及临床严重程度密切相关。这些多态性可以部分解释这些疾病的病理严重程度的异质性。至于骨骼，我们证明p42/44和p38 MAP激酶级联在casr刺激的有丝分裂反应中发挥关键作用。此外，我们还获得了表明CaSR在调节成骨细胞功能中的功能作用的数据。少

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