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

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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