title: Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization.
abstract: Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D [1,25(OH)(2)D], which can elicit calcium mobilization from bone when intestinal calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)(2)D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)(2)D not only increases calcium release from bone, but also inhibits calcium incorporation in bone.
authors.affiliation: Clinical and Experimental Endocrinology, KU Leuven, Leuven, Belgium.
authors.forename: Liesbet
authors.initials: L
authors.lastname: Lieben
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Masuyama
authors.forename: Sophie
authors.initials: S
authors.lastname: Torrekens
authors.forename: Riet
authors.initials: R
authors.lastname: Van Looveren
authors.forename: Jan
authors.initials: J
authors.lastname: Schrooten
authors.forename: Pieter
authors.initials: P
authors.lastname: Baatsen
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Lafage-Proust
authors.forename: Tom
authors.initials: T
authors.lastname: Dresselaers
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
authors.forename: Mark B
authors.initials: MB
authors.lastname: Meyer
authors.forename: J Wesley
authors.initials: JW
authors.lastname: Pike
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
mesh_terms: D000042:Absorption; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000378:metabolism; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D002113:Calcification, Physiologic / Q000187:drug effects* / Q000235:genetics; D002118:Calcium / Q000097:blood* / Q000378:metabolism; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D028061:Phosphate Transport Proteins / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D014807:Vitamin D / Q000494:pharmacology*
chemical_list: D050071:Bone Density Conservation Agents; D028061:Phosphate Transport Proteins; D018167:Receptors, Calcitriol; C410982:ank protein, mouse; D014807:Vitamin D; D010727:Phosphoric Diester Hydrolases; D002118:Calcium