Background: Patients suffering from Crohn's disease (CD) show increased incidence of low bone mineral density. Investigating this complication is difficult because the exact etiology of CD remains elusive. Mice carrying a deletion in the tumor necrosis factor (TNF) AU-rich elements (ARE) are reported as a model for human CD and are characterized by elevated TNF-α levels and inflammations in the terminal ileum. To evaluate whether these mice have a Ca2+handling problem, this study analyzed the Ca2+homeostasis in heterozygous TNFΔAREmice (TNFΔARE/+) in comparison to wildtype littermates. Methods: Beside serum Ca2+and vitamin D levels, the expression of Ca2+transporters was analyzed in intestine, kidney and bone using quantitative real-time PCR, Western blot and immunohistochemistry. Bone scans were performed to measure bone parameters. Results: Ca2+transporters in duodenum (TRPV6, calbindin-D9K, PMCA1b) and kidney (TRPV5, calbindin-D28K, NCX1) showed significantly reduced mRNA expression levels in TNPΔARE/+mice, except for renal TRPV5. In bone, only calbindin-D9KmRNA displayed a significant down-regulation. These findings were supported by declined duodenal calbindin-D9Kand renal calbindin-D28Kprotein values. Likely, this down-regulation of Ca2+transporters in TNPΔARE/+mice is mediated by the 58 ± 9% reduction in serum 1,25(OH)2D3levels. Diminished expression of Ca2+transporters combined with unchanged serum Ca2+levels assumes Ca2+loss from bone to compensate for the body's overall Ca2+shortage. Indeed, microcomputed tomography scanning demonstrated reduced trabecular and corticol bone thickness and volume in TNFΔARE/+mice. This finding is further supported by increased total deoxypyridinoline in serum. Conclusions: Our results imply that TNFΔARE/+mice have a disturbed Ca2+homeostasis characterized by reduced duodenal and renal Ca2+transporters, diminished 1,25(OH)2D3levels, and increased bone resorption associated with profound bone abnormalities. Copyright

Additional Metadata
Keywords Calcium, IBD, Osteoporosis, TRPV5, TRPV6
Persistent URL dx.doi.org/10.1002/ibd.20385, hdl.handle.net/1765/30183
Citation
Huybers, S, Apostolaki, M, van der Eerden, B.C.J, Kollias, G, Naber, T.H.J, Bindels, R.J.M, & Hoenderop, J.G.J. (2008). Murine TNFΔARE Crohn's disease model displays diminished expression of intestinal Ca2+ tansporters. Inflammatory Bowel Diseases, 14(6), 803–811. doi:10.1002/ibd.20385