The parathyroid
hyperplasia secondary to
kidney disease is associated with enhanced expression of the growth promoter
transforming growth factor-alpha (
TGF-alpha).
TGF-alpha stimulates growth through activation of its receptor, the
epidermal growth factor receptor (EGFR), normally expressed in the parathyroid glands. Because enhanced coexpression of
TGF-alpha and EGFR causes aggressive cellular growth, these studies utilized highly specific inhibitors of EGFR
tyrosine kinase, a step mandatory for
TGF-alpha-induced EGFR activation, to assess the contribution of growth signals from enhanced expression of
TGF-alpha exclusively or both
TGF-alpha and EGFR to the rapid parathyroid growth induced by
kidney disease and exacerbated by high-
phosphorus (P) and low-
calcium (Ca) diets in rats. The enhancement in parathyroid gland weight and proliferating activity (
proliferating cell nuclear antigen/Ki67) induced by
kidney disease and aggravated by either high P or low Ca intake, within the first week after 5/6
nephrectomy, in rats, coincided with simultaneous increases (2- to 3-fold) in
TGF-alpha and EGFR content. Conversely, prevention of the increases in both
TGF-alpha and EGFR paralleled the efficacy of either P restriction or high-Ca intake in ameliorating
uremia-induced parathyroid
hyperplasia. More importantly, suppression of
TGF-alpha/EGFR signaling, through prophylactic administration of potent and highly selective inhibitors of
ligand-induced EGFR activation, completely prevented both high-P- and low-Ca-induced parathyroid
hyperplasia as well as
TGF-alpha self-upregulation. Thus enhanced parathyroid
TGF-alpha/EGFR expression, self-upregulation, and growth signals occur early in
kidney disease, are aggravated by low-Ca and high-P intake, and constitute the main pathogenic mechanism of the severity of parathyroid
hyperplasia.