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 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 calcium-sensing receptor (CaSR) and secretes parathyroid hormone (PTH) in response to hypocalcemia.2Brown E.M. Gamba G. Riccardi D. et al.Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.Nature. 1993; 366: 575-580Crossref PubMed Scopus (2258) Google Scholar,3Lewin E. Wang W. Olgaard K. Reversibility of experimental secondary hyperparathyroidism.Kidney Int. 1997; 52: 1232-1241Abstract Full Text PDF PubMed Scopus (45) Google Scholar PTH acts primarily on bone to release calcium from bone storage and on the kidney to enhance renal calcium reabsorption and increase 1,25(OH)2-vitamin D synthesis, which increases intestinal calcium absorption. In addition to extracellular Ca2+, the parathyroid gland also responds to changes in plasma phosphate (p-P), recently shown to be mediated via an effect of P on the CaSR,4Centeno P.P. Herberger A. Mun H.-C. et al.Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.Nat Commun. 2019; 10: 4693Crossref PubMed Scopus (52) Google Scholar activation of the vitamin D receptor, fibroblast growth factor 23 (FGF23) via fibroblast growth factor receptor 1 (FGFR1) in combination with FGFR1 cofactor Klotho and recently proposed to be affected by leptin.4Centeno P.P. Herberger A. Mun H.-C. et al.Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.Nat Commun. 2019; 10: 4693Crossref PubMed Scopus (52) Google Scholar, 5Nielsen P.K. Feldt-Rasmussen U. Olgaard K. A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells.Nephrol Dial Transplant. 1996; 11: 1762-1768Crossref PubMed Scopus (134) Google Scholar, 6Mace M.L. Gravesen E. Nordholm A. et al.Fibroblast growth factor (FGF) 23 regulates the plasma levels of parathyroid hormone in vivo through the FGF receptor in normocalcemia, but not in hypocalcemia.Calcif Tissue Int. 2018; 102: 85-92Crossref PubMed Scopus (15) Google Scholar, 7Kim A. et by vitamin D receptor through in the parathyroid hormone gene PubMed Scopus Google Scholar, et directly parathyroid hormone PubMed Scopus Google Scholar PTH and are P reabsorption in the renal et is not for the and of PubMed Scopus Google Scholar PTH secretion exhibits a diurnal variation with the in and G. et parathyroid hormone circadian rhythm is clinical 1997; PubMed Scopus Google A. Gravesen E. et rhythm of A and related of in normal and uremic 2019; PubMed Scopus Google Scholar The parathyroid glands are not controlled by a as in glands and are to use mechanisms for a circadian variation in hormone E. et the response of PTH to a in parathyroid Int. Full Text Full Text PDF PubMed Scopus Google Scholar, E. et in the parathyroid glands by receptor in normal and uremic Int. Full Text Full Text PDF PubMed Scopus Google Scholar, Olgaard K. et hormone and the parathyroid hormone response to in with parathyroid PubMed Scopus Google Scholar PTH gene contains an in and A. et by vitamin D receptor through in the parathyroid hormone gene PubMed Scopus Google Scholar E-box are known of the circadian clock and and D. et of the in the circadian PubMed Scopus Google Scholar The circadian clock is an that operates with a of to rhythms in hormone secretion, metabolism, and cell A. A. The circadian of cell PubMed Scopus Google Scholar The suprachiasmatic nucleus in the central circadian rhythm for of locomotor activity and the peripheral and central via and However, in addition to this central a molecular clock has been found in a of peripheral A. mechanisms and of circadian PubMed Scopus Google Scholar the of the circadian clock is the which with for to E-box to of the genes and D. Wang et for of in peripheral circadian PubMed Scopus Google Scholar The and to the nucleus and with to their and an transcriptional-translational feedback of the circadian PubMed Scopus Google Scholar feedback induction of et receptor circadian the of the circadian Full Text Full Text PDF PubMed Scopus Google Scholar and which in In regulates the clock a cycle of regulates the activity of the genes by and of et clock in the in circadian by Full Text Full Text PDF PubMed Scopus Google Scholar in a circadian which is to and the of the W. et by regulates and circadian gene expression in peripheral 2018; Full Text Full Text PDF PubMed Scopus Google Scholar not cycle but is in of the circadian PubMed Scopus Google Scholar The circadian clock regulates an to 10% of all genes expressed in peripheral et and circadian gene expression in and PubMed Scopus Google G. et and rhythms of control circadian in PubMed Scopus Google Scholar by of the molecular clock levels from to secretion and is W. et by regulates and circadian gene expression in peripheral 2018; Full Text Full Text PDF PubMed Scopus Google et to circadian rhythm of Full Text Full Text PDF PubMed Scopus Google Scholar, is a central for circadian control of and Full Text Full Text PDF PubMed Scopus Google Scholar, et and of the circadian clock in PubMed Scopus Google Scholar The circadian is entrained by which are primarily via feeding et of the circadian clock in the by PubMed Scopus Google Scholar The circadian clock has been in control of the cell cycle a of induction of Wee1 for of Cyclin the et of the circadian clock for of cell in PubMed Scopus Google Scholar induction of and the E. et circadian A. PubMed Scopus Google A. et circadian clock is a of expression and Full Text Full Text PDF PubMed Scopus Google Scholar and regulation of p27, Cyclin D1, and for through circadian and the cell Full Text Full Text PDF PubMed Scopus Google Scholar, A. et regulates cell growth and PubMed Scopus Google Scholar, et circadian gene an important in cell growth and control in Full Text Full Text PDF PubMed Scopus Google Scholar, et circadian gene an important in and response in Full Text Full Text PDF PubMed Scopus Google Scholar is in the parathyroid gland normal with an of normal parathyroid in and in Parathyroid cell proliferation in the effect of and of phosphate and 1996; PubMed Scopus Google Scholar This increases in secondary hyperparathyroidism by chronic kidney disease is a cause of bone disease and and in with a combination of and changes in the parathyroid glands that are in increased PTH secretion, and in parathyroid that parathyroid PTH Int. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar and are in the of the parathyroid A. et with and regulates parathyroid hormone expression and parathyroid PubMed Scopus Google et parathyroid to of the factor PubMed Scopus Google Scholar but to parathyroid was found to parathyroid cell and proliferation in A. et regulates the of parathyroid in 2019; 14: PubMed Scopus Google Scholar and and MafB may a in K. et factor MafB may an important in secondary hyperparathyroidism.Kidney Int. 2018; Full Text Full Text PDF PubMed Scopus Google E. et a master of parathyroid gland and regulation in Full Text Full Text PDF PubMed Scopus Google Scholar The is the to the internal molecular circadian clock in the parathyroid gland and whether an internal molecular circadian clock is related to the circadian rhythm of and parathyroid function. we the of deregulation of a circadian clock in the of in and bone and the impact of deregulation of the clock in to uremic in cycle and were for and parathyroid glands were for gene and expression of clock of the gene expression was by to a of and was for and circadian rhythm was found for and and of the circadian rhythmicity of clock genes of clock genes by in the parathyroids from rats, and to is a with control P is the P from is a with control P is the P from is a with control P is the P from is a with control P is the P from is a with control P is the P from is a with control P is the P from is a with control P is the P from is a with control P is the P from is a with control P is the P from chronic kidney in since shown as is a with control P is the P from in a chronic kidney in since shown as circadian rhythmicity of clock in the parathyroid glands with a of with that of the gene expression of for an operating circadian clock on the was found in with and in the parathyroid glands not diurnal variation as previously shown by and G. et parathyroid hormone circadian rhythm is clinical 1997; PubMed Scopus Google A. Gravesen E. et rhythm of A and related of in normal and uremic 2019; PubMed Scopus Google Scholar and was by in the and the Parathyroid expression of the gene diurnal variation The gene expression of important regulators of PTH secretion was Klotho and expression rhythmicity the expression of FGFR1 cofactor Klotho was not and rhythmicity The gene expression of regulators circadian clock was Cyclin D1, p27, and Wee1 expression rhythmicity as Cyclin rhythmicity was found for the regulators of parathyroid proliferation and PTH secretion, and expression was examined and rhythmicity was for MafB and Gata3 but not for Parathyroid was by acute induction of in vivo in the E. Wang W. Olgaard K. Reversibility of experimental secondary hyperparathyroidism.Kidney Int. 1997; 52: 1232-1241Abstract Full Text PDF PubMed Scopus (45) Google E. et the response of PTH to a in parathyroid Int. Full Text Full Text PDF PubMed Scopus Google E. et in the parathyroid glands by receptor in normal and uremic Int. Full Text Full Text PDF PubMed Scopus Google Scholar the in to since was in the were from a in to the response to PTH secretion not the were to the of cycle and feeding for and were feeding was to the for were and parathyroid glands for and gene expression examined Significant rhythmicity was for with to that found in 1 were Significant rhythmicity was found also for and not and not the to the the of and and and circadian that that of with to feeding In rhythmicity with a also feeding and found a rhythmicity and of the to that of P and PTH the of the circadian rhythm in the gene expression of the parathyroid circadian clock genes in feeding a in with in feeding the circadian rhythm of with but not the of and and were by by for for are in and the control and the In we found increased and as well as was was from with a of and of and parathyroid glands for and that gene expression of was in as was gene expression of cell a proliferation expressed circadian rhythm of genes related to regulation and proliferation is disturbed in the uremic parathyroid The gene and proliferation not circadian The levels increased in regulators Wee1 and Cyclin rhythmicity in normal parathyroid glands, which is in chronic kidney disease the expression of is of parathyroid cell proliferation MafB and Gata3 circadian rhythm in normal which is in diurnal Circadian rhythmicity was by and the P are shown with P are with normal and is since The in is on of the the Circadian clock genes were in uremic with control with of of was found rhythmicity of in uremic rats, in to in control of the gene that in the of rhythmicity was to as to the normal for and Significant in the were found for and a increase in was found for of cell cycle of the circadian clock were in the circadian rhythm of Wee1 and Cyclin was and of Wee1 and was found was found for deregulation was found for regulators of parathyroid proliferation and PTH the circadian rhythm of MafB and Gata3 was in and and were In a was found and the circadian of cell cycle Wee1 from in which the of and was and parathyroid glands were and are in and Significant deregulation was found for and expression was not affected by uremia to the after of in In was on parathyroid glands from normal and with and by in were found. A increase in of of the was found in this in clock and as by a of W. et by regulates and circadian gene expression in peripheral 2018; Full Text Full Text PDF PubMed Scopus Google is a central for circadian control of and Full Text Full Text PDF PubMed Scopus Google Scholar was found for of in parathyroid glands of uremic with that of control rats. is of The has been shown to have a circadian clock. The impact of on the circadian clock has not previously been investigated. of in of and vitamin D in not E. Nordholm A. et of of in uremic with 2018; PubMed Scopus Google Scholar from from the Gravesen E. M.L. et of chronic uremia on the of the by PubMed Scopus (31) Google Scholar in with that from the of control have been to The on circadian genes and genes of circadian clock are in A of and a of and were found in was also in was D and factor are and with known to be controlled by the circadian clock, to their factor regulated of circadian PubMed Scopus Google and were all in the uremic The circadian regulators Wee1 and were Cyclin was in the uremic aorta. was found for clock and genes in the uremic receptor locomotor circadian clock circadian clock circadian clock receptor receptor of promoter cell was by uremia and with The gene were by in a was by uremia and with The gene were by In was for of the rhythmicity of the expression of the circadian clock genes in an of with vitamin D with control rats. In control rats, rhythmicity of and was and not the which was by In of and was was a in the for was found This is the an internal circadian clock operating in the parathyroid is that the expression of the clock and rhythmicity in the parathyroid The circadian expression were to that found in the in the as not of the circadian PubMed Scopus Google Scholar Circadian are in peripheral entrained primarily by to the the of in the parathyroid we feeding from by to the of the for for the of the circadian clock to In on peripheral the for a in the of the circadian clock to after a in feeding has been et feeding circadian in peripheral from the central in the suprachiasmatic 14: PubMed Scopus Google Scholar feeding the of and is known to primarily to an of phosphate in the et with by in 2018; PubMed Scopus Google Scholar This the of the of in in feeding and after feeding in the feeding Circadian rhythmicity of might be controlled by the circadian clock in the et to circadian rhythm of Full Text Full Text PDF PubMed Scopus Google Scholar known to be entrained by et of the circadian clock in the by PubMed Scopus Google Scholar This might the in the of feeding to the the of but not the of circadian clock genes in the This that feeding minimally the circadian clock in the parathyroid in to peripheral et of the circadian clock in the by PubMed Scopus Google et feeding circadian in peripheral from the central in the suprachiasmatic 14: PubMed Scopus Google A. et of circadian in peripheral by PubMed Scopus Google et to circadian rhythms with feeding 2019; Full Text Full Text PDF PubMed Scopus Google Scholar the cycle and the parathyroid circadian clock cycle it that PTH secretion is primarily regulated by a circadian clock. A expression of the gene in the parathyroid glands the and in the parathyroid response to and this As it is not how rhythmicity is the rhythmicity might be to as have been shown for et cell of genes PubMed Scopus Google Scholar PTH has a in addition to effect and P has been shown to stimulate PTH secretion, directly via and P.P. Herberger A. Mun H.-C. et al.Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.Nat Commun. 2019; 10: 4693Crossref PubMed Scopus (52) Google P.K. Feldt-Rasmussen U. Olgaard K. A direct effect in vitro of phosphate on PTH release from bovine parathyroid tissue slices but not from dispersed parathyroid cells.Nephrol Dial Transplant. 1996; 11: 1762-1768Crossref PubMed Scopus (134) Google et cell proliferation in normal and chronic renal rats. The of and vitamin PubMed Scopus Google Scholar, Parathyroid hormone gene expression in PubMed Google Scholar, E. et regulation of parathyroid hormone by PubMed Scopus Google Scholar and by which the P.P. Herberger A. Mun H.-C. et al.Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.Nat Commun. 2019; 10: 4693Crossref PubMed Scopus (52) Google Parathyroid hormone gene expression in PubMed Google E. et regulation of parathyroid hormone by PubMed Scopus Google Scholar might that the diurnal variation in from of the diurnal variation in As an of we found that the of the P cycle and that of PTH in feeding by and a impact on the expression of the circadian clock genes in the parathyroid Cyclin D1, p27, and are regulators, which are controlled by the circadian clock. Significant rhythmicity of the gene expression of Wee1 and Cyclin was found in the parathyroid glands and this was in a of cell cycle Wee1 and was found of uremia and of uremia to also Cyclin and with for to the This might the of the circadian cell cycle gene the gene expression of and was affected by The in of in an of regulation of the circadian clock machinery in the which is disturbed in This might from in from a in the of The is known to be and the glands for were a and not are in with from an by et et of in and secondary 2018; PubMed Scopus Google Scholar examined the gene expression in parathyroids and found of in and of and in hyperparathyroidism. However, the circadian rhythmicity in the parathyroid glands and in uremia as found in the have not been shown of in has been to of parathyroid hyperplasia and G. G. and levels in of and secondary PubMed Scopus Google Scholar K. K. et and vitamin D receptor in the hyperplasia in with secondary hyperparathyroidism.Kidney Int. Full Text Full Text PDF PubMed Scopus Google Scholar is a which is for of the parathyroid glands, but also with expression in has been proposed to parathyroid cell and proliferation in A. et regulates the of parathyroid in 2019; 14: PubMed Scopus Google Scholar and to expression of et receptor expression is regulated by in parathyroid PubMed Scopus Google et the calcium-sensing receptor effect of a associated with 85-92Crossref PubMed Scopus Google Scholar the Gata3 and MafB for parathyroid and PTH that parathyroid PTH Int. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, A. et with and regulates parathyroid hormone expression and parathyroid PubMed Scopus Google Scholar, et parathyroid to of the factor PubMed Scopus Google K. Gata3 with and MafB to parathyroid hormone gene expression by with PubMed Scopus Google Scholar In normal parathyroid glands, we found rhythmicity in the expression of Gata3 and the gene of and to that of Wee1 were found in normal and uremic glands, which may a regulation by the circadian clock, which directly is to of on the expression of the of in have been with increased expression in and E. et a master of parathyroid gland and regulation in Full Text Full Text PDF PubMed Scopus Google Scholar and also with expression in and expression in G. G. of a master gene of parathyroid gland in of PubMed Scopus (31) Google Scholar has MafB in the of uremic in MafB parathyroid proliferation and PTH K. et factor MafB may an important in secondary hyperparathyroidism.Kidney Int. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar In the an increase in the gene expression of and Gata3 and was found in the of increased parathyroid by an increased gene and by increased gene expression after of This was by a of and MafB of parathyroid expression of et receptor expression is regulated by in parathyroid PubMed Scopus Google et the calcium-sensing receptor effect of a associated with 85-92Crossref PubMed Scopus Google Scholar which is in and to of the parathyroid glands to extracellular calcium and it might be important to the regulation of this factor activity by the circadian clock in future is an the the deregulation of circadian clock that of the cell cycle whether the growth of the tissue the circadian that of the circadian rhythm may cause abnormal cell growth and an increased of have cell proliferation in the glands and to et circadian gene an important in cell growth and control in Full Text Full Text PDF PubMed Scopus Google et circadian gene an important in and response in Full Text Full Text PDF PubMed Scopus Google Scholar In this is the to an internal circadian clock machinery operating in the parathyroid The of this clock is not entrained by feeding. and secondary parathyroid growth are associated with severe deregulation of the circadian clock and cell cycle and tissue growth. also to of the circadian clock and downstream genes in the uremic that of the circadian clock machinery is an important of were for A of were in a cycle and a and vitamin with to and to were was from and parathyroid glands were by and in in the in all were not to by and the feeding was to the from to for and were as were and growth were and parathyroid glands were were was by of by a via a in the were for of and and from a in the E. Wang W. Olgaard K. Reversibility of experimental secondary hyperparathyroidism.Kidney Int. 1997; 52: 1232-1241Abstract Full Text PDF PubMed Scopus (45) Google E. et the response of PTH to a in parathyroid Int. Full Text Full Text PDF PubMed Scopus Google E. et in the parathyroid glands by receptor in normal and uremic Int. Full Text Full Text PDF PubMed Scopus Google Scholar The of was by an of was by E. et of calcium-sensing receptor in parathyroids severe secondary hyperparathyroidism is by an kidney PubMed Scopus Google G. et parathyroid expression of in uremic Int. Full Text Full Text PDF PubMed Scopus Google Scholar in rats. normal were as vitamin parathyroid glands and were for were to control was by E. et of calcium-sensing receptor in parathyroids severe secondary hyperparathyroidism is by an kidney PubMed Scopus Google Scholar and parathyroid glands were and and was in by and for A. K. et fibroblast growth factor receptor the increased expression in acute and chronic PubMed Scopus Google Scholar Parathyroid glands were from to in and from control rats. was in by and vitamin Gravesen E. M.L. et of chronic uremia on the of the by PubMed Scopus (31) Google Scholar the renal and the was from uremic as well as from control and have and to the of the have previously been Gravesen E. M.L. et of chronic uremia on the of the by PubMed Scopus (31) Google Scholar the the of to on circadian molecular and were the Parathyroid and gene were by and and expression was by and the The and be found in the and the of parathyroid glands from normal and uremic were by the were Core were to a the the of the The is Significant rhythm is found the of not the was K. an for in PubMed Scopus Google Scholar was for uremic and control were as P The was by the and in with for the to for was from The and The and and The and was in the the of with

Topics & Concepts