TY - JOUR
T1 - Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis
AU - Lieben, L.
AU - Benn, B. S.
AU - Ajibade, D.
AU - Stockmans, I.
AU - Moermans, K.
AU - Hediger, M. A.
AU - Peng, J. B.
AU - Christakos, S.
AU - Bouillon, R.
AU - Carmeliet, G.
N1 - Funding Information: The authors thank S. Torrekens, N. Smets, R. Van Looveren, E. Vanherck and I. Jans (Katholieke Universiteit Leuven) for their assistance. This work was supported by a grant from the Fund for Scientific Research-Flanders (FWO: G.0508.05 and G.0587.09 ), Center of Excellence (Mosaic, EF/05/08 ) and the National Institute of Health ( DK38961-21 ). L. Lieben is a fellow of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen).
PY - 2010/8
Y1 - 2010/8
N2 - Energy-dependent intestinal calcium absorption is important for the maintenance of calcium and bone homeostasis, especially when dietary calcium supply is restricted. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a crucial regulator of this process and increases the expression of the transient receptor potential vanilloid 6 (Trpv6) calcium channel that mediates calcium transfer across the intestinal apical membrane. Genetic inactivation of Trpv6 in mice (Trpv6-/-) showed, however, that TRPV6 is redundant for intestinal calcium absorption when dietary calcium content is normal/high and passive diffusion likely contributes to maintain normal serum calcium levels. On the other hand, Trpv6 inactivation impaired the increase in intestinal calcium transport following calcium restriction, however without resulting in hypocalcemia. A possible explanation is that normocalcemia is maintained at the expense of bone homeostasis, a hypothesis investigated in this study. In this study, we thoroughly analyzed the bone phenotype of Trpv6-/- mice receiving a normal (-1%) or low (-0.02%) calcium diet from weaning onwards using micro-computed tomography, histomorphometry and serum parameters. When dietary supply of calcium is normal, Trpv6 inactivation did not affect growth plate morphology, bone mass and remodeling parameters in young adult or aging mice. Restricting dietary calcium had no effect on serum calcium levels and resulted in a comparable reduction in bone mass accrual in Trpv6+/+ and Trpv6-/- mice (-35% and 45% respectively). This decrease in bone mass was associated with a similar increase in bone resorption, whereas serum osteocalcin levels and the amount of unmineralized bone matrix were only significantly increased in Trpv6-/- mice. Taken together, our findings indicate that TRPV6 contributes to intestinal calcium transport when dietary calcium supply is limited and in this condition indirectly regulates bone formation and/or mineralization.
AB - Energy-dependent intestinal calcium absorption is important for the maintenance of calcium and bone homeostasis, especially when dietary calcium supply is restricted. The active form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], is a crucial regulator of this process and increases the expression of the transient receptor potential vanilloid 6 (Trpv6) calcium channel that mediates calcium transfer across the intestinal apical membrane. Genetic inactivation of Trpv6 in mice (Trpv6-/-) showed, however, that TRPV6 is redundant for intestinal calcium absorption when dietary calcium content is normal/high and passive diffusion likely contributes to maintain normal serum calcium levels. On the other hand, Trpv6 inactivation impaired the increase in intestinal calcium transport following calcium restriction, however without resulting in hypocalcemia. A possible explanation is that normocalcemia is maintained at the expense of bone homeostasis, a hypothesis investigated in this study. In this study, we thoroughly analyzed the bone phenotype of Trpv6-/- mice receiving a normal (-1%) or low (-0.02%) calcium diet from weaning onwards using micro-computed tomography, histomorphometry and serum parameters. When dietary supply of calcium is normal, Trpv6 inactivation did not affect growth plate morphology, bone mass and remodeling parameters in young adult or aging mice. Restricting dietary calcium had no effect on serum calcium levels and resulted in a comparable reduction in bone mass accrual in Trpv6+/+ and Trpv6-/- mice (-35% and 45% respectively). This decrease in bone mass was associated with a similar increase in bone resorption, whereas serum osteocalcin levels and the amount of unmineralized bone matrix were only significantly increased in Trpv6-/- mice. Taken together, our findings indicate that TRPV6 contributes to intestinal calcium transport when dietary calcium supply is limited and in this condition indirectly regulates bone formation and/or mineralization.
KW - 1,25(OH)D
KW - Bone remodeling
KW - Hyperosteoidosis
KW - Intestinal calcium absorption
KW - TRPV6
UR - https://www.scopus.com/pages/publications/77955984248
UR - https://www.scopus.com/pages/publications/77955984248#tab=citedBy
U2 - 10.1016/j.bone.2010.04.595
DO - 10.1016/j.bone.2010.04.595
M3 - Article
C2 - 20399919
SN - 8756-3282
VL - 47
SP - 301
EP - 308
JO - Bone
JF - Bone
IS - 2
ER -