title: Extra-intestinal calcium handling contributes to normal serum calcium levels when intestinal calcium absorption is suboptimal.
abstract: The active form of vitamin D, 1,25(OH)2D, is a crucial regulator of calcium homeostasis, especially through stimulation of intestinal calcium transport. Lack of intestinal vitamin D receptor (VDR) signaling does however not result in hypocalcemia, because the increased 1,25(OH)2D levels stimulate calcium handling in extra-intestinal tissues. Systemic VDR deficiency, on the other hand, results in hypocalcemia because calcium handling is impaired not only in the intestine, but also in kidney and bone. It remains however unclear whether low intestinal VDR activity, as observed during aging, is sufficient for intestinal calcium transport and for mineral and bone homeostasis. To this end, we generated mice that expressed the Vdr exclusively in the gut, but at reduced levels. We found that ~15% of intestinal VDR expression greatly prevented the Vdr null phenotype in young-adult mice, including the severe hypocalcemia. Serum calcium levels were, however, in the low-normal range, which may be due to the suboptimal intestinal calcium absorption, renal calcium loss, insufficient increase in bone resorption and normal calcium incorporation in the bone matrix. In conclusion, our results indicate that low intestinal VDR levels improve intestinal calcium absorption compared to Vdr null mice, but also show that 1,25(OH)2D-mediated fine-tuning of renal calcium reabsorption and bone mineralization and resorption is required to maintain fully normal serum calcium levels.
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Liesbet
authors: L
authors: Lieben
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Lieve
authors: L
authors: Verlinden
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Ritsuko
authors: R
authors: Masuyama
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Sophie
authors: S
authors: Torrekens
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium.
authors: Karen
authors: K
authors: Moermans
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, KU Leuven, Leuven, Belgium.
authors: Luc
authors: L
authors: Schoonjans
authors: Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, KU Leuven, Leuven, Belgium.
authors: Peter
authors: P
authors: Carmeliet
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium. Electronic address: geert.carmeliet@med.kuleuven.be.
authors: Geert
authors: G
authors: Carmeliet
mesh_terms: D000375:Aging / Q000097:blood / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active; D016723:Bone Remodeling / Q000502:physiology; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood* / Q000378:metabolism*; D002136:Calcium, Dietary / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D002136:Calcium, Dietary; D010281:Parathyroid Hormone; D053245:RANK Ligand; D018167:Receptors, Calcitriol; C505689:Tnfsf11 protein, mouse; D002117:Calcitriol; D002118:Calcium
keywords: Bone; Calcium homeostasis; Intestine; Kidney; Vitamin D