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

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

Research output: Contribution to journalArticle

198 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1803-1815
Number of pages13
JournalJournal of Clinical Investigation
Volume122
Issue number5
DOIs
StatePublished - May 1 2012
Externally publishedYes

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Physiologic Calcification
Vitamin D
Calcium
Bone and Bones
Calcitriol Receptors
Calcium Signaling
Intestinal Absorption
Intestines
Serum
Osteocytes
Bone Matrix
Bone Remodeling
Metabolic Bone Diseases
Bone Fractures
Osteoblasts
Knockout Mice
Homeostasis
Hormones

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Lieben, L., Masuyama, R., Torrekens, S., Van Looveren, R., Schrooten, J., Baatsen, P., ... Carmeliet, G. (2012). Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. Journal of Clinical Investigation, 122(5), 1803-1815. https://doi.org/10.1172/JCI45890

Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. / Lieben, Liesbet; Masuyama, Ritsuko; Torrekens, Sophie; Van Looveren, Riet; Schrooten, Jan; Baatsen, Pieter; Lafage-Proust, Marie Hélène; Dresselaers, Tom; Feng, Jian Q.; Bonewald, Lynda; Meyer, Mark B.; Pike, J. Wesley; Bouillon, Roger; Carmeliet, Geert.

In: Journal of Clinical Investigation, Vol. 122, No. 5, 01.05.2012, p. 1803-1815.

Research output: Contribution to journalArticle

Lieben, L, Masuyama, R, Torrekens, S, Van Looveren, R, Schrooten, J, Baatsen, P, Lafage-Proust, MH, Dresselaers, T, Feng, JQ, Bonewald, L, Meyer, MB, Pike, JW, Bouillon, R & Carmeliet, G 2012, 'Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization', Journal of Clinical Investigation, vol. 122, no. 5, pp. 1803-1815. https://doi.org/10.1172/JCI45890
Lieben, Liesbet ; Masuyama, Ritsuko ; Torrekens, Sophie ; Van Looveren, Riet ; Schrooten, Jan ; Baatsen, Pieter ; Lafage-Proust, Marie Hélène ; Dresselaers, Tom ; Feng, Jian Q. ; Bonewald, Lynda ; Meyer, Mark B. ; Pike, J. Wesley ; Bouillon, Roger ; Carmeliet, Geert. / Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 5. pp. 1803-1815.
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