Role of phosphorus in the pathogenesis of secondary hyperparathyroidism.
Secondary hyperparathyroidism (SH) and hyperplasia of the parathyroid glands (PTG) are universal complications in patients with CRF. In early renal failure, reduction in serum calcitriol and moderate decreases in ionized calcium contribute to greater synthesis and secretion of PTH. As renal disease progresses, a reduction in parathyroid expression of vitamin D receptor and calcium receptor renders the PTG more resistant to both calcitriol and calcium. High dietary phosphorus (P), independent of calcium and calcitriol, further enhances uremia-induced PTG hyperplasia and PTH synthesis and secretion, the latter by posttranscriptional mechanisms. Once SH develops, dietary P restriction can return the high serum PTH levels toward normal, however, parathyroid hyperplasia persists. Studies in our laboratory identified 2 of the mechanisms involved in the opposing effects of high and low dietary P content on PTG growth. Whereas high dietary P increases parathyroid expression of transforming growth factor alpha (TGFalpha), a growth promoter, P restriction induces the cyclin-dependent kinase inhibitor p21, an inducer of growth arrest. Both effects of P are specific for the PTG. No increase in either protein was observed in liver or intestine. TGFalpha induction of hyperplasia involves binding to the epidermal growth factor receptor and activation of mitogen activated protein (MAP) kinases cascades. p21 blocks progression through the cycle and cell division by inactivating cyclin/cyclin-dependent kinase complexes. Preventing hyperphosphatemia and elevated Ca x P product in renal failure not only ameliorates the progression of SH and bone disease but also the morbidity and mortality resulting from vascular calcification.
Slatopolsky
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Renal Division, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA. eslatopo@imgate.wustl.edu
Brown
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Dusso
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D000818:Animals; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000097:blood / Q000209:etiology*; D006965:Hyperplasia; D007676:Kidney Failure, Chronic / Q000150:complications; D010280:Parathyroid Glands / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism; D010710:Phosphates / Q000097:blood; D016226:Phosphorus, Dietary / Q000008:administration & dosage*
D010281:Parathyroid Hormone; D010710:Phosphates; D016226:Phosphorus, Dietary