p21^WAF1 and TGF-α mediate parathyroid growth arrest by vitamin D and high calcium

Background. High dietary phosphorus (P) worsens uremia-induced parathyroid (PT) hyperplasia through increases in the growth promoter transforming growth factor-alpha (TGF-α). In contrast, P restriction prevents PT hyperplasia by inducing the cell cycle inhibitor p21. Since 1,25(OH)₂D₃-antiproliferative action in various cell types involve increases in p21, we studied whether induction of p21 by 1,25(OH)₂D₃ or the vitamin D analog, 19-Nor-1,25(OH)₂D₂, could counteract the PT hyperplasia induced by high dietary P in early uremia. Methods. Normal (N) and uremic (U; 5/6 nephrectomized) female Sprague-Dawley rats were fed high P (HP), low P (LP) or high Ca (HCa) diets and administered intraperitoneally (IP) either vehicle or vitamin D metabolites for seven days, as follows: N-HP; U-HP + vehicle; U-HP + 1,25(OH)₂D₃ (4 ng/ day); U-HP + 19-Nor-1,25(OH)₂D₂ (30 ng/day); U-LP; U-HCa. Serum PTH and PT gland weight assessed secondary hyperparathyroidism. Immunohistochemical quantitation of two markers of mitotic activity, Ki67 and PCNA measured PT hyperplasia. Immunohistochemical expression of PT p21 and TGF-α addressed potential mechanisms regulating PT cell growth. Results. 1,25(OH)₂D₃ and 19-Nor-1,25(OH)₂D₂ were effective in suppressing both PTH secretion and PT hyperplasia induced by uremia and high dietary P independent of increases in ionized Ca. Both vitamin D compounds enhanced PT p21 expression and prevented high P-induced increases in PT TGF-α content. Induction of PT p21 and reduction of TGF-α content also occurred when uremia-induced PT hyperplasia was suppressed by high dietary Ca. Conclusions. In early uremia, vitamin D suppression of high P-induced PT hyperplasia and high dietary Ca arrest of PT growth involve induction of PT p21 and prevention of increases in TGF-α.