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HORMONES AND SIGNALING

Prednisolone-induced Ca²⁺ malabsorption is caused by diminished expression of the epithelial Ca²⁺ channel TRPV6

¹Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre; and ²Departments of Gastroenterology, Radboud University Nijmegen Medical Centre and Internal Medicine, Hilversum Hospital, Nijmegen, The Netherlands

Submitted 18 July 2006 ; accepted in final form 5 August 2006

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.

1,25-dihydroxyvitamin D₃; duodenum; epithelial calcium channel 2; calcium transporter 1

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