Hypothalamic regulation of parathyroid hormone rhythm via circadian oscillators and neural circuits

Abstract

All the organisms exist approximately 24-hour rhythms in physiological activities which are controlled by the central ‘master clock’. The suprachiasmatic nucleus (SCN) of the hypothalamus, known as the central circadian clock, plays a crucial role in the production of circadian rhythms. The complex SCN neural network involved in regulation of cell-autonomous and rhythmic physiological processes. Evidence from human studies show that the secretion of parathyroid hormone (PTH) has diurnal rhythm in healthy people while normal PTH rhythm was absent in osteoporosis patients. Although the molecular basis of clock genes that regulate clock-controlled physiological activities are well studied, it is still unknown whether and how PTH rhythm is regulated. In this study, we aim to investigate the organizational rules on how the central nervous signals are transformed into circadian rhythms of PTH secretion. In addition, this study will also clarify the importance of maintaining autologous rhythm of PTH and provide new insights into the function of PTH from a neurological perspective and a new strategy for the treatment of bone-related diseases. Here we show that parathyroid hormone secretion in mice exhibits a diurnal rhythm with a bimodal pattern which will be altered under external cues, such as light, sleep, physiological disease. The parathyroid gland and SCN clock both control the rhythmic secretion of PTH and the intrinsic rhythm of PTH is important for maintaining bone homeostasis. Loss of PTH rhythm can seriously dampened bone homeostasis in mice which will be alleviated by compensation of PTH rhythm. In addition, the rhythmic secretion of PTH is controlled by master clock SCN which can significantly affect the secretion rhythm of PTH without changing the daily average secretion level. Peripheral PTH signals can directly activate neurons in rhythmically related brain regions of the hypothalamus such as SCN and PVN. The hypothalamus integrates certain signals to feedback to the SCN and make downstream rhythmic regulation. The SCN is directly connected to the peripheral parathyroid gland and there are rhythm signals in the cerebrospinal fluid that can be sensed and feedback through hypothalamus. Moreover, there is a subset of neurons expressing PTH/PTH1R located in core region and central region of SCN. The PTH positive neurons in SCN played a pivotal role for the perception and regulation of the PTH rhythm. Furthermore, the neural circuits from GadSCN to vGlutPVN are essential for circadian rhythmic regulation of PTH secretion. PVN receives inputs from SCN and subsequently project axons to neurohypophysis to effect or regulate endocrine control of the PTH, which provide a functional link between central nervous system and peripheral organs. Our findings reveal that how central clock and peripheral clock coordinate with each other and regulate circadian rhythm of PTH secretion, which could provide insights into the generation of daily PTH rhythms and demonstrate the importance for maintaining bone metabolism.