Pathophysiologic mechanisms of the abnormal parathyroid hormone secretion

终末期肾功能衰竭继发性甲状旁腺功能亢进和肾性骨营养不良的处理是一个重要的临床问题。了解甲状旁腺激素分泌和甲状旁腺细胞增殖的病理生理机制是发展新的、理想的方法的必要条件。为此，我们研究了钙感应受体（Casr）的功能。我们已经确定了新生儿严重甲状旁腺功能亢进的几个突变。为了阐明这些突变体Casr的功能，我们在HEK 293细胞中表达了位点定向诱变产生的突变体，并通过测量细胞内钙浓度和肌醇三磷酸的产生来评估其对细胞外钙浓度变化的反应。在这些实验中，我们证实了这些突变体是无功能的。这一结果在手，我们下一步探索Casr在细胞增殖中的作用以及细胞外条件对受体功能的影响。结果表明受体功能与细胞增殖密切相关，并提示胞外葡萄糖浓度在其功能中的重要作用。此外，我们发现Casr基因的遗传多态性与继发性甲状旁腺功能亢进的严重程度密切相关。

The management of secondary hyperparathyroidism and renal osteodystrophy in end-stage renal failure is an important clinical problem. For the development of new and ideal methodologies, it is essential to know the pathophysiologic mechanisms of the parathyroid hormone secretion and the parathyroid cellular proliferation. To this aid, we have investigated the function of the calcium sensing receptor (Casr).We have already identified several mutations in neonatal severe hyperparathyroidism. To clarify the function of these mutant Casr, the mutants produced by site directed mutagenesis were expressed in HEK 293 cell and the response to the change in extracellular calcium concentration was evaluated by measuring intracellular calcium concentration and inositol tris phosphate production. In these experiments, we confirmed that these mutants were functionless. This result in hands, we next explored the effects of Casr in the cellular proliferation and the effects of extracellular conditions on the function of the receptor. The results clearly indicated the close relationship between the function of receptor and the cellular proliferation, and suggested importance of the extracellular glucose concentration in its function. Moreover, we identified close relationship between the genetic polymorphism in the Casr gene and the severity of the secondary hyperparathyroidism.