Parathyroid diseases and animal models

Abstract

CIRCULATING CALCIUM AND PHOSPHATE ARE TIGHTLY REGULATED BY THREE HORMONES: the active form of vitamin D (1,25-dihydroxyvitamin D), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). PTH acts to stimulate a rapid increment in serum calcium and has a crucial role in calcium homeostasis. Major target organs of PTH are kidney and bone. The oversecretion of the hormone results in hypercalcemia, caused by increased intestinal calcium absorption, reduced renal calcium clearance, and mobilization of calcium from bone in primary hyperparathyroidism. In chronic kidney disease, secondary hyperparathyroidism of uremia is observed in its early stages, and this finally develops into the autonomous secretion of PTH during maintenance hemodialysis. Receptors in parathyroid cells, such as the calcium-sensing receptor, vitamin D receptor, and FGF receptor (FGFR)-Klotho complex have crucial roles in the regulation of PTH secretion. Genes such as Cyclin D1, RET, MEN1, HRPT2, and CDKN1B have been identified in parathyroid diseases. Genetically engineered animals with these receptors and the associated genes have provided us with valuable information on the patho-physiology of parathyroid diseases. The application of these animal models is significant for the development of new therapies.

Keywords: CKD; CaR; FGF-23; Klotho; PTH; calcitriol; cinacalcet; hyperparathyroidism.

Figure 1

Feedback loops in Ca and P homeostasis, modified from previous reports (Imanishi et al., 2009a,b). There are feedback loops between Ca²⁺, P, 1,25-(OH)₂D, FGF-23, and PTH. Ca²⁺, 1,25-(OH)₂D, and FGF-23 suppress PTH secretion, whereas P overload accelerates it. The P overload does not always cause hyperphosphatemia, except for in some conditions such as chronic kidney disease.

Figure 2

The sigmoidal curve of the PTH-Ca relationship, modified from a previous report (Imanishi, 2002). The analyses of PTH secretions inhibited by extracellular Ca in vitro revealed the sigmoidal relationship of the PTH-Ca relationship. Setpoint, the Ca concentration causing half-maximal inhibition of PTH secretion, is an indicator of sensitivity of parathyroid cells to extracellular Ca by CaR. (A) The relationship in healthy subjects was fitted to a symmetrical sigmoidal curve. (B) The normal sigmoidal curve will shift upward when the secretory cell number is increased, without changing its setpoint. (C) An altered sigmoidal curve is observed in human parathyroid adenomas, refractory SHPT, by changing the setpoint to the right. In the case of severe setpoint shift, PTH secretion is persistent even at high Ca concentration: so-called “autonomous” PTH secretion. An altered PTH-Ca relationship was also observed in PTH-cyclin D1 transgenic mice (Imanishi et al., 2001, 2009a). (D) Administration of cinacalcet or activating mutation of CaR observed in autosomal dominant hypocalcemia increases the CaR sensitivity to serum Ca. Activations of CaR result in the PTH-Ca relationship curve moving to the left.