Received April 2, 2007
Accepted on September 4, 2007

BASIC RESEARCH

EGFR Activation Increases Parathyroid Hyperplasia and Calcitriol Resistance in Kidney Disease

Maria Vittoria Arcidiacono ^*, Tetsuhiko Sato ^*, Daniel Alvarez-Hernandez ^*, Jing Yang ^*, Masanori Tokumoto ^*, Ignacio Gonzalez-Suarez ^*, Yan Lu ^*, Yoshihiro Tominaga , Jorge Cannata-Andia , Eduardo Slatopolsky ^*, and Adriana S. Dusso ^*1

*Renal Division, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri; Nagoya Daini Red Cross Hospital, Nagoya, Japan; and Division of Bone and Mineral Metabolism, Hospital Universitario Central de Asturias, Oviedo, Spain

¹ To whom correspondence should be addressed. E-mail: adusso{at}im.wustl.edu.

	Abstract

Calcitriol, acting through vitamin D receptors (VDR) in the parathyroid, suppresses parathyroid hormone synthesis and cell proliferation. In secondary hyperparathyroidism (SH), VDR content is reduced as hyperplasia becomes more severe, limiting the efficacy of calcitriol. In a rat model of SH, activation of the EGF receptor (EGFR) by TGF- is required for the development of parathyroid hyperplasia, but the relationship between EGFR activation and reduced VDR content is unknown. With the use of the same rat model, it was found that pharmacologic inhibition of EGFR activation with erlotinib prevented the upregulation of parathyroid TGF-, the progression of growth, and the reduction of VDR. Increased TGF-/EGFR activation induced the synthesis of liver-enriched inhibitory protein, a potent mitogen and the dominant negative isoform of the transcription factor CCAAT enhancer binding protein-, in human hyperplastic parathyroid glands and in the human epidermoid carcinoma cell line A431, which mimics hyperplastic parathyroid cells. Increases in liver-enriched inhibitory protein directly correlated with proliferating activity and, in A431 cells, reduced VDR expression by antagonizing CCAAT enhancer binding protein- transactivation of the VDR gene. Similarly, in nodular hyperplasia, which is the most severe form of SH and the most resistant to calcitriol therapy, higher TGF- activation of the EGFR was associated with an 80% reduction in VDR mRNA levels. Thus, in SH, EGFR activation is the cause of both hyperplastic growth and VDR reduction and therefore influences the efficacy of therapy with calcitriol.