¹Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel

Correspondence: Justin Silver, Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hospital, PO Box 12000, Jerusalem 911220, Israel. E-mail: silver@huji.ac.il

Received 10 June 2008; Revised 31 August 2008; Accepted 14 October 2008; Published online 7 January 2009.

Abstract

The phosphate (Pi) retention in patients with chronic kidney disease leads to secondary hyperparathyroidism (2HPT). 2HPT is the physiological response of the parathyroid not only to Pi retention but also to decreased synthesis of 1,25(OH)₂ vitamin D, and the attendant hypocalcemia. 2HPT is characterized by increased PTH synthesis, secretion, and parathyroid cell proliferation. Extracellular fluid (ECF) Ca²⁺ is recognized by the parathyroid calcium receptor and a small decrease in the ECF Ca²⁺ results in relaxation of the calcium receptor and allows the unrestrained secretion and synthesis of PTH and in the longer term, parathyroid cell proliferation. Both 1,25(OH)₂ vitamin D and fibroblast growth factor 23 inhibit PTH gene expression and secretion. Secondary hyperparathyroidism can initially be controlled by a single therapeutic intervention, such as a Pi-restricted diet, a calcimimetic, or an active vitamin D analog. In this review we discuss the mechanisms whereby Pi regulates the parathyroid. Pi has a direct effect on the parathyroid which requires intact parathyroid tissue architecture. The effect of Pi, as of Ca²⁺, on PTH gene expression is post-transcriptional and involves the regulated interaction of parathyroid cytosolic proteins to a defined cis acting sequence in the PTH mRNA. Changes in serum Ca²⁺ or Pi regulate the activity of trans acting interacting proteins in the parathyroid, which alters their binding to a defined 26 nucleotide cis acting instability sequence in the PTH mRNA 3'-untranslated region. The trans factors are either stabilizing or destabilizing factors and their regulated binding to the PTH cis acting element determines the PTH mRNA half-life. The responses of the parathyroid to changes in serum Pi are now being revealed but the sensing mechanisms remain a mystery.