Pathogenic mechanisms for parathyroid hyperplasia

• Published in: Kidney international Vol. 70; no. S102; pp. S8 - S11
• Main Authors: Dusso, A.S., Sato, T., Arcidiacono, M.V., Alvarez-Hernandez, D., Yang, J., Gonzalez-Suarez, I., Tominaga, Y., Slatopolsky, E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2006; Elsevier Limited
• Subjects: Animals; Calcitriol - therapeutic use; Calcium, Dietary - administration & dosage; Calcium, Dietary - metabolism; Disease Models, Animal; Drug Resistance - drug effects; EGFR; Gene Expression Regulation - drug effects; Humans; Hyperplasia - drug therapy; Hyperplasia - etiology; Hyperplasia - metabolism; Hyperplasia - pathology; Hypocalcemia; Kidney Diseases - complications; Kidney Diseases - drug therapy; Kidney Diseases - metabolism; Kidney Diseases - pathology; Parathyroid Glands - metabolism; Parathyroid Glands - pathology; Phosphorus, Dietary - administration & dosage; Phosphorus, Dietary - metabolism; Rats; secondary hyperparathyroidism; Signal Transduction - drug effects; TGFα; vitamin D; vitamin D receptor; Vitamins - therapeutic use; TGFα; vitamin D receptor; secondary hyperparathyroidism; vitamin D; EGFR
• ISSN: 0085-2538; 0098-6577; 1523-1755
• DOI: 10.1038/sj.ki.5001595

Parathyroid hyperplasia is the cause of parathyroid gland enlargement in kidney disease (KD). Hypocalcemia, hyperphosphatemia, and vitamin D deficiency are critical contributors to the worsening of the hyperplastic parathyroid growth induced by KD. Reproduction of the features of human KD in the 5/6 nephrectomized rat model has shown that 80% of the mitogenic signals induced by KD in parathyroid cells that are aggravated by either high phosphate (P) or low calcium (Ca) diets occurred within 5 days after the onset of KD. Enhanced parathyroid expression of the potent growth promoter transforming growth factor alpha (TGFα) and its receptor, the epidermal growth factor receptor (EGFR), was identified as the main cause of parathyroid hyperplasia in experimental KD. Indeed, administration of highly specific EGFR-tyrosine kinase inhibitors (TKI), which block downstream signaling from TGFα-activated EGFR, completely prevented high P- and low Ca-induced parathyroid hyperplasia in early KD, as well as the severe progression of high P-induced parathyroid growth in established secondary hyperparathyroidism, the latter characterized by marked TGFα and EGFR overexpression in the parathyroid glands. More importantly, the suppression of signals downstream from TGFα binding to EGFR with EGFR-TKI treatment also revealed that TGFα self-upregulation in the parathyroid glands is the main determinant of the severity of the hyperplastic growth, and that enhanced TGFα activation of EGFR mediates the reduction in parathyroid vitamin D receptor levels thereby causing resistance to both the antiproliferative and parathyroid hormone-suppressive properties of calcitriol therapy.