A molecular circadian clock operates in the parathyroid gland and is disturbed in chronic kidney disease associated bone and mineral disorder

Abstract

Circadian rhythms in metabolism, hormone secretion, cell cycle and locomotor activity are regulated by a molecular circadian clock with the master clock in the suprachiasmatic nucleus of the central nervous system. However, an internal clock is also expressed in several peripheral tissues. Although about 10% of all genes are regulated by clock machinery an internal molecular circadian clock in the parathyroid glands has not previously been investigated. Parathyroid hormone secretion exhibits a diurnal variation and parathyroid hormone gene promoter contains an Ebox like element, a known target of circadian clock proteins. Therefore, we examined whether an internal molecular circadian clock is operating in parathyroid glands, whether it is entrained by feeding and how it responds to chronic kidney disease. As uremia is associated with extreme parathyroid growth and since disturbed circadian rhythm is related to abnormal growth, we examined the expression of parathyroid clock and clockregulated cell cycle genes in parathyroid glands of normal and uremic rats. Circadian clock genes were found to be rhythmically expressed in normal parathyroid glands and this clock was minimally entrained by feeding. Diurnal regulation of parathyroid glands was next examined. Significant rhythmicity of fibroblast-growth-factorreceptor-1, MafB and Gata3 was found. In uremic rats, deregulation of circadian clock genes and the cell cycle regulators, Cyclin D1, c-Myc, Wee1 and p27, which are influenced by the circadian clock, was found in parathyroid glands as well as the aorta. Thus, a circadian clock operates in parathyroid glands and this clock and downstream cell cycle regulators are disturbed in uremia and may contribute to dysregulated parathyroid proliferation in secondary hyperparathyroidism.

New Aspects of the Kidney in the Regulation of Fibroblast Growth Factor 23 (FGF23) and Mineral Homeostasis

“…Still, plasma levels of Klotho do not express circadian rhythmicity, as demonstrated by our group [31]. Furthermore, plasma phosphate and PTH have circadian rhythms that depend on the feeding pattern [32]. This phenomenon should be taken into consideration when interpreting the circulating levels of FGF23.…”

“…The circadian rhythms in hormonal levels have a systemic impact on all aspects of physiology. Results from our laboratory showed the existence of a circadian rhythm of plasma FGF23 levels ( Figure 2A) [31,32]. The physiological importance of FGF23 rhythmicity remains, however, to be established.…”

“…Rats were acclimatized to standard conditions of 12:12h light:dark cycle and ad libitum feeding for 2 weeks and so blood samples were obtained at a 4 h interval for 24 h. Feeding was then restricted to the light phase (inactive phase in nocturnal rodents) for 4 weeks and the blood sampling was repeated. Feeding restricted to the inactive phase markedly shifted the phase of plasma FGF23 together with that of plasma PTH and phosphate, still exhibiting significant circadian rhythms but at a reverse-phase pattern that mirrored the one of rats with continuous access to feeding ( Figure 2) [32]. As such, the intestine-bone axis might have an impact on the circadian rhythmicity of plasma FGF23 levels and on the circadian rhythmicity of hormones and factors that are regulating FGF23 secretion on long term basis.…”

“…We further examined the circadian clock operating the parathyroid gland in normal and in CKD rats suffering from secondary hyperparathyroidism. It was shown that an internal molecular circadian clock operates in the parathyroids and that a circadian rhythmicity of genes, regulating cell cycle was demonstrated [32]. In the hyperplastic glands, key genes of the circadian clock machinery were deregulated including shifted or abolished rhythmicity over the 24 h [32].…”

“…It was shown that an internal molecular circadian clock operates in the parathyroids and that a circadian rhythmicity of genes, regulating cell cycle was demonstrated [32]. In the hyperplastic glands, key genes of the circadian clock machinery were deregulated including shifted or abolished rhythmicity over the 24 h [32]. Parathyroid tissue from patients with primary or secondary hyperparathyroidism has also shown deregulation of clock genes [103].…”