title: A model of calcium homeostasis in the rat.
abstract: We developed a model of calcium homeostasis in the rat to better understand the impact of dysfunctions such as primary hyperparathyroidism and vitamin D deficiency on calcium balance. The model accounts for the regulation of calcium intestinal uptake, bone resorption, and renal reabsorption by parathyroid hormone (PTH), vitamin D3, and Ca2+itself. It is the first such model to incorporate recent findings regarding the role of the calcium-sensing receptor (CaSR) in the kidney, the presence of a rapidly exchangeable pool in bone, and the delayed response of vitamin D3synthesis. Accounting for two (fast and slow) calcium storage compartments in bone allows the model to properly predict the effects of bisphophonates on the plasma levels of Ca2+([Ca2+]p), PTH, and vitamin D3Our model also suggests that Ca2+exchange rates between plasma and the fast pool vary with both sex and age, allowing [Ca2+]pto remain constant in spite of sex- and age-based hormonal and other differences. Our results suggest that the inconstant hypercalciuria that is observed in primary hyperparathyroidism can be attributed in part to counterbalancing effects of PTH and CaSR in the kidney. Our model also correctly predicts that calcimimetic agents such as cinacalcet bring down [Ca2+]pto within its normal range in primary hyperparathyroidism. In addition, the model provides a simulation of CYP24A1 inactivation that leads to a situation reminiscent of infantile hypercalcemia. In summary, our model of calcium handling can be used to decipher the complex regulation of calcium homeostasis.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France; and.|Department of Pharmacology and Toxicology, University of Lausanne, and Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Granjon
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, and Service of Nephrology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bonny
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMRS 1138, CNRS ERL 8228, Centre de Recherche des Cordeliers, Paris, France; and aurelie.edwards@crc.jussieu.fr.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Edwards
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002762:Cholecalciferol / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D006961:Hyperparathyroidism / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008954:Models, Biological; D010281:Parathyroid Hormone / Q000378:metabolism; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D014808:Vitamin D Deficiency / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002762:Cholecalciferol; D002118:Calcium
keywords: PTH; calcium; homeostasis; mathematical model; vitamin D3