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Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D–induced inhibition of bone mineralization
Liesbet Lieben, … , Roger Bouillon, Geert Carmeliet
Liesbet Lieben, … , Roger Bouillon, Geert Carmeliet
Published April 23, 2012
Citation Information: J Clin Invest. 2012;122(5):1803-1815. https://doi.org/10.1172/JCI45890.
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Research Article

Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D–induced inhibition of bone mineralization

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Abstract

Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D [1,25(OH)2D], 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)2D 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)2D not only increases calcium release from bone, but also inhibits calcium incorporation in bone.

Authors

Liesbet Lieben, Ritsuko Masuyama, Sophie Torrekens, Riet Van Looveren, Jan Schrooten, Pieter Baatsen, Marie-Hélène Lafage-Proust, Tom Dresselaers, Jian Q. Feng, Lynda F. Bonewald, Mark B. Meyer, J. Wesley Pike, Roger Bouillon, Geert Carmeliet

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Figure 7

Molecular mechanism of 1,25(OH)2D-induced suppression of mineralization.

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Molecular mechanism of 1,25(OH)2D-induced suppression of mineralization....
(A–D, H, and I) Gene expression analysis by qRT-PCR in in vitro–differentiated osteoblasts after treatment with vehicle, 10–8 M 1,25(OH)2D3, and 2.5 × 10–8 M PTH for 24 hours. Values denote mRNA copy number normalized to that of Hprt (see Methods). n = 6. (E) ChIP-seq tag density profiles for VDR (blue) and RXR (green) after treatment with vehicle or 10–7 M 1,25(OH)2D3 (1,25D) for 3 hours in MC3T3-E1 cells. Data centered around the Enpp3 and Ank peak genomic locus are shown, with arrows indicating the direction of gene transcription. ChIP-seq tag densities were normalized to 1 × 107 tags; tag maximum for the data is shown at top left of each track. (F) qRT-PCR quantification of ChIP-DNA, obtained from MC3T3-E1 cells treated with vehicle or 1,25(OH)2D3 (10–7 M for 3 hours) prior to ChIP with VDR, RXR, and nonspecific IgG antibodies, with primers flanking the TSS of Enpp1 (1 TSS), the +58-kb peak in and the TSS of Enpp3 (3 +58kb and 3 TSS, respectively), the TSS of and the +63-kb peak in Ank, and a control sequence. Shown is 1 representative experiment of 3. (G) Femoral mRNA levels analyzed by qRT-PCR. n = 8. *P < 0.05, **P < 0.01, #P < 0.001 vs. vehicle-treated Vdr+/+, 1-way ANOVA followed by Fisher’s LSD multiple-comparison test; §§P < 0.01, §§§P < 0.001 vs. Vdrint+.
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