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

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 E-box 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 clock-regulated 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-factor-receptor-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. 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 E-box 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 clock-regulated 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-factor-receptor-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. Translational StatementCircadian rhythms in metabolism, hormone secretion, cell cycle, and locomotor activity are regulated by a molecular circadian clock. Disruption of the circadian rhythm may cause serious health problems and abnormal cell growth. Secondary hyperparathyroidism is a severe complication of chronic kidney disease associated with increased morbidity and mortality, and the control of parathyroid hyperplasia is a clinical challenge. This article describes the existence of an internal molecular circadian clock that is operating in the parathyroid gland and which is disturbed in chronic kidney disease. Deregulation of the circadian clock in the parathyroids might therefore potentially call for the use of chronotherapy in future clinical studies. Circadian rhythms in metabolism, hormone secretion, cell cycle, and locomotor activity are regulated by a molecular circadian clock. Disruption of the circadian rhythm may cause serious health problems and abnormal cell growth. Secondary hyperparathyroidism is a severe complication of chronic kidney disease associated with increased morbidity and mortality, and the control of parathyroid hyperplasia is a clinical challenge. This article describes the existence of an internal molecular circadian clock that is operating in the parathyroid gland and which is disturbed in chronic kidney disease. Deregulation of the circadian clock in the parathyroids might therefore potentially call for the use of chronotherapy in future clinical studies. Circadian rhythms are controlled by the molecular clock mechanisms and have a systemic impact on all aspects of physiology, including hormonal secretion, metabolism, and cell cycle. Core clock genes and their products are involved in transcriptional-translational feedback loops and are revealed as important regulators of organ function. The possible existence of an internal circadian clock machinery in the parathyroid gland has not previously been examined. Calcium homeostasis is maintained primarily by the parathyroid glands.1Lewin E. Wang W. Olgaard K. Rapid recovery of plasma ionized calcium after acute induction of hypocalcaemia in parathyroidectomized and nephrectomized rats.Nephrol Dial Transplant. 1999; 14: 604-609Crossref PubMed Scopus (31) Google Scholar The parathyroid gland senses minor changes in extracellular ionized calcium (Ca2+) via the ca