Elevated parathyroid hormone (PTH) levels cause osteitis fibrosa, bone loss and cardiovascular complications, all of which contribute significantly to increased morbidity and mortality in renal failure. Hyperplasia of PTH-producing cells is a major cause of high serum PTH levels. While it is known that hypocalcemia, hyperphosphatemia, and vitamin D deficiency promote parathyroid (PT) hyperplasia in renal failure, the underlying mechanisms are poorly understood. Our studies of PT growth in uremic rats fed a high P diet have shown that activation of the TGFa/EGFR pathway is a major contributor to PT hyperplasia. Inhibition of EGFR activation by AG1478, a highly specific EGFR-tyrosine kinase inhibitor (TKI), reduces uremia- and high P-induced PT hyperplasia by 60%. This finding raises the hypothesis that the potent inhibition of PT hyperplasia by vitamin D could result from downregulation of TGFa/EGFR growth signals. In fact, vitamin D suppresses the PT cell growth induced by uremia and high P by preventing increases in TGFa and EGFR. In vitro, vitamin D arrests the growth driven by EGFR overexpression by antagonizing EGFR-activation of ERKI/2 and transactivation of cyclin D1, and potentiates the growth arrest induced by maximally inhibitory doses of AG1478. The latter demonstrates antiproliferative vitamin D actions that are EGFR-independent. The overall goal of this proposal is to characterize the antagonistic interactions between vitamin D and TGFa/EGFR and their relevance in the pathogenesis and treatment of parathyroid hyperplasia. To this end, we propose to use TKI, 1,25D and combined therapy to identify: 1) Actual contribution of activation of the autocrine TGFa/EGFR-growth loop to parathyroid hyperplasia and vitamin D resistance in early and advanced renal failure. 2) EGFR-dependent and independent mechanisms mediating vitamin D-suppression of parathyroid hyperplasia. 3) Molecular mechanisms mediating vitamin D-inhibition of EGFR-growth signals in EGFR overexpressing cells. 4) Mechanisms mediating vitamin D-potentiation of TKI-inhibition of growth in EGFR overexpressing cells. By identifying pathogenic mechanisms, these studies should help design more effective therapies for secondary hyperparathyroidism. ? ?
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