The role of vitamin D in the pathogenesis: Role of phosphate

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Hyperphosphatemia due to decreased glomerular filtration rate is an important factor in the pathogenesis of secondary HPT.    Elevated serum phosphate levels induce secondary HPT through indirect and direct mechanisms. In addition, hy­perphosphatemia inhibits 1,25(OH)₂D production, with subsequent hypocalcemia.

The direct effects of phosphorus have been demonstrated both in vitro and in vivo studies. High phosphorus concentrations stimulate PTH secretion in intact rat parathyroid glands. Unfortunately, the in vitro effects of phosphorus on PTH secre­tion could be observed in intact parathyroid tissue prepara­tions, but not isolated, dispersed parathyroid cells. Re­cently, several studies have shown that phosphate may regu­late parathyroid function at post-transcriptional level, as it im­proves PTH mRNA stability through binding of parathyroid cy- tosolic proteins to the 3′-UTR and especially to the terminal 60 nucleotides of PTH mRNA.

Two weeks after 5/6 nephrectomy in rats, uremia-induced mi- totic activity is further enhanced by high dietary phosphate, but prevented by phosphorus restriction. In contrast to the mi- togenic effects of hyperphosphatemia, dietary phosphorus re­striction appears to counteract the proliferative signals induced by uremia, thus preventing parathyroid cell replication and the increase in parathyroid gland size.

Recent studies on the effects of dietary phosphate on parathy­roid gland growth demonstrated that the low phosphorus-in­duction of p21 (an inhibitor of kinases of the cell-cycle) mRNA and protein content in parathyroid glands contributes to the an- tiproliferative effects of phosphate restriction on uremia-in­duced parathyroid cell growth. In this uremic rat model, the temporal increases in p21 protein expression correlate in­versely with the parathyroid levels of a marker of mitotic activi­ty, the proliferating nuclear cell antigen (PCNA). In the search for the mitogenic stimuli triggered by high dietary phosphate, we next focused on transforming growth factor-a (TGFa). TGFa, known to promote growth not only in malignant transformation but also in normal tissues, is increased in hyperplastic and adenomatous human parathyroid glands. High phosphate diet worsens uremia-induced parathyroid hy­perplasia by increasing parathyroid expression of TGFa. The rapid return of parathyroid TGFa content to normal after phos­phate restriction suggests that low phosphorus may counteract uremia-induced parathyroid cell growth not only through induc­tion of p21 expression, but also by preventing the increase in parathyroid TGFa.

Increase in parathyroid TGFa induces cell growth through au­tocrine and paracrine mechanisms through activation of its re­ceptor, the epidermal growth factor receptor (EGFR). In human parathyroid glands, Gogusev et al. demonstrated the presence of EGFR protein in 4 out of 5 adenomas, in 13 out of 15 tissue samples of hyperplasia secondary to renal fail­ure, and in most samples of normal parathyroid tissue. No dif­ferences in the expression patterns were observed between groups. However, studies in 104 human hyperplastic parathy­roid glands, which failed to detect EGFR protein, showed high­er EGFR mRNA expression in carcinoma and primary hyperplasia compared to adenomas and hyperplasia secondary to renal failure. Beat the drug companies and buy generic viagra online

The concept that co-expression of TGFa and EGFR could con­tribute to non-neoplastic parathyroid hyperplasia led us to ex­amine the dietary-phosphate regulation of parathyroid EGFR expression in rat parathyroid glands. Similarly to the changes in TGFa expression, high dietary phosphate increases parathy­roid EGFR content to above normal levels, while phosphorus restriction prevented the increases in EGFR levels. These findings indicate that the uremia-induced parathyroid co- expression of TGFa and its receptor, EGFR, acts as a mito- genic signal, which can be blunted by phosphate restriction and counteracted through the induction of p21. These new in­sights into the molecular mechanisms of parathyroid hyperpla­sia suggest that, in addition to phosphate restriction or use of phosphate binders, therapeutic approaches focusing on induc­tion of p21 and inactivation of TGFa/EGFR growth-promoting signals may slow down the progression of secondary HPT.