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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 May 1, 2012; First published April 23, 2012
Citation Information: J Clin Invest. 2012;122(5):1803-1815. https://doi.org/10.1172/JCI45890.
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Category: 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 9

Vdroc– mice are protected against 1,25(OH)2D3-induced mineralization defects.

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Vdroc– mice are protected against 1,25(OH)2D3-induced mineralization de...
Vdroc+ and Vdroc– mice were treated with vehicle or 1,25(OH)2D3 for 1 week. (A) Serum calcium levels. n = 4–6. (B and C) μCT analysis of BV/TV (B) and Ct.Th (C). n = 8. (D) Serum CTx levels. n = 4–6. (E) TRAP staining showing osteoclasts (arrows) on the trabeculae and quantification of the osteoclast surface. n = 5. Scale bar: 50 μm. (F) Goldner-stained trabeculae (arrows denote osteoids) with quantification of osteoid surface and thickness. n = 5. Scale bar: 50 μm. (G) Analysis of dynamic bone formation parameters by sequential calcein injections showing a normal mineralization pattern in Vdroc– mice with the formation of single (arrow) and double (double-sided arrow) labels. Scale bar: 20 μm. (H and I) mRNA expression in the femur analyzed by qRT-PCR. n = 5–8. Values denote mRNA copy number normalized to that of Hprt (see Methods). #P < 0.05, 1,25(OH)2D3 vs. vehicle, §P < 0.05, Vdroc– vs. Vdroc+, 2-way ANOVA followed by Fisher’s LSD multiple-comparison test.
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