As pointed out above, calcitriol reduces parathyroid cell proliferation by decreasing the expression of the early gene, c-myc. This gene modulates the progression from G1 to S phase in cell cycle. A decrease in plasma calcitriol and/or a disturbance of its action at the level of the parathyroid cell, which are both frequently observed in uremic patients, may cause progression into the cell cycle and disinhibition of c-myc expression. Another mode of action involves the cyclin kinase inhibitor p21WAF1. Calcitriol has long been shown to induce the differential expression of p21WAF1 in the myelo-monocytic cell line U937 and to activate the p21 gene transcriptionally in a VDR-dependent, but p53-independent, manner . Slatopolsky’s group were the first to show that the administration of calcitriol to uremic rats enhanced parathyroid p21 expression and prevented high phosphate-induced increase in parathyroid TGF-α content . Calcitriol’s stimulatory effect on parathyroid p21 expression was subsequently confirmed by others . Slatopolsky’s group further reported that calcitriol altered membrane trafficking of the epithelial growth factor receptor (EGFR, which binds both EGF and TGF-α) and down-regulated EGFR growth signaling . Induction of p21 and reduction of TGF-αcontent in the parathyroid glands also occurred when uremia-induced parathyroid hyperplasia was suppressed by high dietary Ca. The mechanisms by which a phosphate-rich diet and hyperphosphatemia induce parathyroid hyperplasia, and conversely a phosphate-poor diet and hypophosphatemia inhibit parathyroid tissue growth, have also been explored by this group in a detailed fashion. Thus, Dusso et al showed that feeding a low phosphate diet to uremic rats increased parathyroid p21 gene expression through a vitamin D-independent mechanism . When administering a high phosphate diet there was however no reduction in p21 expression. In this condition, they observed an increase in parathyroid tissue TGF-α expression and a direct correlation between this expression and parathyroid cell proliferation rate. This finding is in line with the previous observation by our group of de novo TGF-α expression in severely hyperplastic parathyroid tissue of uremic patients . Although these findings provide more insight into the pathways by which changes in phosphate intake, and ultimately variations in extracellular phosphate concentration, control parathyroid tissue growth, the exciting question of the transmembrane signal transduction mechanism and subsequent nuclear events triggered by phosphate remains yet to be answered. Finally, suppression of TGF-alpha/EGFR signaling through the administration of selective inhibitors of ligand-induced EGFR activation, completely prevented both high-phosphate- and low-Ca-induced parathyroid hyperplasia as well as TGF-alpha self-upregulation.

In addition to p21 and TGF-α , a number of other growth factors and inhibitors may be involved in polyclonal parathyroid hyperplasia. Thus, PTHrp has also been proposed as a posssible growth suppressor in the human parathyroid . PTHrp, and probably PTH itself, also exert an inhibitory effect on PTH secretion by acting via a negative feedback loop on the PTH/PTHrp receptor 1 (PTH-R1) which appears to be expressed in the parathyroid cell membrane as well . Table 1 summarizes various changes in gene and growth factor expression which are potentially involved in the parathyroid tissue hyperplasia of 2° uremic hyperparathyroidism. Gcm2 was recently identified as a master regulatory gene of parathyroid gland development, as Gcm2 knockout mice lack parathyroid glands . Correa et al. found high Gcm2 mRNA expression in human parathyroid glands in comparison with other non-neural tissues and underexpression in parathyroid adenomas but not in lesions of HPT secondary to uremia . It is unknown whether Gcm2 itself is submitted to regulation by other factors.