p21^WAF1 and transforming growth factor-α mediate dietary phosphate regulation of parathyroid cell growth.

The parathyroid (PT) hyperplasia induced by renal failure can be further enhanced by high dietary phosphate (P) or completely abolished by P restriction. To identify potential mechanisms mediating these opposing effects of dietary P on PT growth, this study first focused on p21^WAF1 (p21) because high P reduces while low P enhances serum 1,25-dihydroxyvitamin D, whose potent antiproliferative properties result from the induction of p21. In addition to reducing p21, high P-induced PT growth could result from increased PT expression of the growth promoter transforming growth factor-α (TGF-α), known to be elevated in hyperplastic and adenomatous human PT glands.

The time course for dietary P regulation of PT expression of TGF-α and p21 was assessed for seven days after 5/6 nephrectomy in rats and correlated with the degree of PT hyperplasia and secondary hyperparathyroidism.

In P-restricted 5/6 nephrectomized rats, PT-p21 mRNA and protein increased by day 2, independent of changes in serum 1,25-dihydroxyvitamin D, and remained higher than in the high P counterparts for up to seven days. The PT hyperplasia of the high P group could not be attributed to a reduction of PT-p21 expression from normal control values. Instead, PT–TGF-α protein was higher in uremic rats compared with normal controls and increased further with high dietary P intake. PT levels of proliferating cell nuclear antigen (PCNA), an index of cell mitoses, correlated inversely with p21 and directly with TGF-α. Consistent with these findings, PT gland size and serum PT hormone levels, similar in both dietary groups at day 2, were higher in the high P group by day 5. Induction of p21 by low P and of TGF-α by high P was specific for the PT glands. Dietary P had no effect either on intestinal growth or p21 or TGF-α protein content.

These findings suggest that low P induction of p21 could prevent PT hyperplasia in early uremia, whereas high P enhancement of TGF-α may function as an autocrine signal to stimulate growth further.