title: Prednisolone-induced Ca2+ malabsorption is caused by diminished expression of the epithelial Ca2+ channel TRPV6.
abstract: Glucocorticoids, such as prednisolone, are often used in clinic because of their anti-inflammatory and immunosuppressive properties. However, glucocorticoids reduce bone mineral density (BMD) as a side effect. Malabsorption of Ca2+ in the intestine is supposed to play an important role in the etiology of low BMD. To elucidate the mechanism of glucocorticoid-induced Ca2+ malabsorption, the present study investigated the effect of prednisolone on the expression and activity of proteins responsible for active intestinal Ca2+ absorption including the epithelial Ca2+ channel TRPV6, calbindin-D(9K), and the plasma membrane ATPase PMCA1b. Therefore, C57BL/6 mice received 10 mg/kg body wt prednisolone daily by oral gavage for 7 days and were compared with control mice receiving vehicle only. An in vivo 45Ca2+ absorption assay indicated that intestinal Ca2+ absorption was diminished after prednisolone treatment. We showed decreased duodenal TRPV6 and calbindin-D(9K) mRNA and protein abundance in prednisolone-treated compared with control mice, whereas PMCA1b mRNA levels were not altered. Importantly, detailed expression studies demonstrated that in mice these Ca2+ transport proteins are predominantly localized in the first 2 cm of the duodenum. Furthermore, serum Ca2+ and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] concentrations remained unchanged by prednisolone treatment. In conclusion, these data suggest that prednisolone reduces the intestinal Ca2+ absorption capacity through diminished duodenal expression of the active Ca2+ transporters TRPV6 and calbindin-D(9K) independent of systemic 1,25(OH)2D3.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Hilversum Hospital, Nijmegen, The Netherlands.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Huybers
authors.forename: Ton H J
authors.initials: TH
authors.lastname: Naber
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
mesh_terms: D000818:Animals; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000235:genetics*; D002132:Calcium Radioisotopes; D004195:Disease Models, Animal; D004386:Duodenum / Q000502:physiology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000502:physiology* / Q000503:physiopathology; D008286:Malabsorption Syndromes / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011239:Prednisolone / Q000494:pharmacology*; D064030:S100 Calcium Binding Protein G / Q000235:genetics; D050916:TRPV Cation Channels / Q000187:drug effects / Q000235:genetics*
chemical_list: D064026:Calbindins; D015220:Calcium Channels; D002132:Calcium Radioisotopes; D064030:S100 Calcium Binding Protein G; D050916:TRPV Cation Channels; C446923:Trpv6 protein, mouse; D011239:Prednisolone; D002118:Calcium