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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 3

Increased bone remodeling in Vdrint– mice.

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Increased bone remodeling in Vdrint– mice.
   
(A) Serum CTx levels. n =...
(A) Serum CTx levels. n = 5–8. (B) Sections of the tibia cortex stained for TRAP reactivity, showing osteoclasts in red (arrow). Scale bar: 100 μm. (C) Ratio of RankL mRNA to Opg mRNA in the femur. n = 8. (D) Serum calcium levels in 14-week-old mice after treatment with vehicle or zoledronic acid for 6 weeks. n = 4–8. (E) Serum osteocalcin levels. n = 7. (F) H&E staining demonstrated increased abundance of cuboidal active osteoblasts lining the cortex (arrows) in Vdrint– mice. Scale bar: 50 μm. (G) Gene expression by qRT-PCR in the femur. n = 8. *P < 0.05, #P < 0.001 vs. Vdrint+; §P < 0.05 as indicated by the bracket.

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