Nephrol Dial Transplant (2000) 15 [Suppl 5]: 2–7 Nephrology Dialysis Transplantation II. RECOMMENDATIONS FOR THE MANAGEMENT OF RENAL OSTEODYSTROPHY Molecular mechanisms of secondary hyperparathyroidism Justin Silver Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hospital and Hebrew University Hadassah Medical School, PO Box 12000, Jerusalem 91120, Israel concentration, which is recognized by a seven- Introduction transmembrane-domain receptor with a large extra- cellular amino-terminal region, the calcium-sensing The development of secondary hyperparathyroidism receptor [4]. A decrease in extracellular calcium is a major risk factor for the development of renal concentration leads not only to an increase in PTH osteodystrophy. In cases of chronic renal failure (CRF ) secretion but also to increases in PTH mRNA levels where there is an inadequate increase in parathyroid and parathyroid cell proliferation. Hypocalcaemia hormone (PTH ) secretion, adynamic bone disease may increases PTH secretion in the short term, PTH mRNA develop. There is, therefore, a pressing clinical need to levels in hours and days and parathyroid cell number be able to fine-tune the synthesis and secretion of PTH after a more prolonged stimulus [5–7]. and the compensatory increase necessary in CRF. This requires an understanding of the physiological mechanisms involved in regulating PTH synthesis and secretion. Phosphate regulates the parathyroid independently Vitamin D and the parathyroid of calcium and 1,25 (OH ) 2 D 3 PTH is tropic to the renal synthesis of 1,25-dihydroxy- We have studied the mechanism of the effect of calcium vitamin D 3 (1,25(OH) 2 D 3 ) and there is a well-defined on PTH gene expression and have shown that in vivo feedback loop whereby 1,25(OH) 2 D 3 markedly it is post-transcriptional. Phosphate also regulates the decreases PTH transcription and subsequent secretion. parathyroid. The contribution of hyperphosphataemia The specific 1,25(OH ) 2 D 3 receptor ( VDR) is present to the pathogenesis of the secondary hyperparathyroid- in the parathyroid at a similar concentration to that ism of CRF has been documented for many years [8], in the duodenum, which is the classical vitamin D but it was never possible to separate the effect of target organ [1] (Figure 1). This underscores the hyperphosphataemia from secondary decreases in physiological relevance of the action of 1,25(OH ) 2 D 3 serum calcium and 1,25(OH ) 2 D 3 [9]. This was first on the parathyroid (Figure 2). established by the work in our laboratory of Kilav The effect of 1,25(OH) 2 D 3 is a powerful one in all et al. who succeeded in demonstrating that the effect systems studied. In vivo in the rat, a single small dose of serum phosphate on PTH gene expression and of 1,25(OH) 2 D 3 decreased PTH gene transcription by serum PTH levels was independent of any changes in almost 100% [2]. This effect has an important applica- serum calcium or 1,25(OH ) 2 D 3 [10]. A visual example tion in the management of CRF patients with second- of the powerful effect of phosphate on the parathyroid ary hyperparathyroidism. Less VDR is expressed in is shown in Figure 3. To demonstrate the effect of secondary hyperparathyroidism, especially in nodular phosphate on the parathyroid in vitro, it was imperative hyperplastic regions of the parathyroid [3]. to maintain tissue architecture [11–13]. There was an effect in whole glands or tissue slices but not in Calcium and the parathyroid isolated cells. The parathyroid responds to changes in serum A remarkable characteristic of the parathyroid is phosphate concentration at the level of secretion, gene its sensitivity to small changes in serum calcium expression and cell proliferation, but by what mechan- ism? We can now provide some of the answers regard- Correspondence and offprint requests to: Professor J. Silver, Hebrew ing the effect of phosphate and calcium on PTH gene University Hadassah Medical School, PO Box 12000, Jerusalem 91120, Israel. expression. © 2000 European Renal Association–European Dialysis and Transplant Association by guest on September 23, 2015 http://ndt.oxfordjournals.org/ Downloaded from