title: Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis.
abstract: 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 D(3) [1,25(OH)(2)D(3)], 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 (approximately 1%) or low (approximately 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.
authors.affiliation: Laboratory of Experimental Medicine and Endocrinology, Katholieke Universiteit Leuven, Leuven, B-3000, Belgium.
authors.forename: L
authors.initials: L
authors.lastname: Lieben
authors.forename: B S
authors.initials: BS
authors.lastname: Benn
authors.forename: D
authors.initials: D
authors.lastname: Ajibade
authors.forename: I
authors.initials: I
authors.lastname: Stockmans
authors.forename: K
authors.initials: K
authors.lastname: Moermans
authors.forename: M A
authors.initials: MA
authors.lastname: Hediger
authors.forename: J B
authors.initials: JB
authors.lastname: Peng
authors.forename: S
authors.initials: S
authors.lastname: Christakos
authors.forename: R
authors.initials: R
authors.lastname: Bouillon
authors.forename: G
authors.initials: G
authors.lastname: Carmeliet
mesh_terms: D000375:Aging / Q000187:drug effects / Q000473:pathology; D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D015220:Calcium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002136:Calcium, Dietary / Q000494:pharmacology*; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects*; D007408:Intestinal Absorption / Q000187:drug effects*; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects; D010710:Phosphates / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002136:Calcium, Dietary; D010710:Phosphates; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C446923:Trpv6 protein, mouse; D002118:Calcium
references.citation: Endocrinology. 1998 Oct;139(10):4391-6
references.pmid: 9751523
references.citation: Am J Physiol. 1998 Feb;274(2):G389-96
references.pmid: 9486194
references.citation: Arch Biochem Biophys. 2004 Dec 15;432(2):152-66
references.pmid: 15542054
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7498-503
references.pmid: 11416220
references.citation: J Clin Invest. 2006 Dec;116(12):3150-9
references.pmid: 17099775
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13324-9
references.pmid: 11687634
references.citation: J Bone Miner Res. 2003 Jul;18(7):1217-26
references.pmid: 12854831
references.citation: Am J Clin Nutr. 2004 Oct;80(4):998-1002
references.pmid: 15447911
references.citation: J Biol Chem. 1999 Aug 6;274(32):22739-46
references.pmid: 10428857
references.citation: J Bone Miner Res. 1997 Jun;12(6):922-8
references.pmid: 9169351
references.citation: Mol Biol Cell. 2008 May;19(5):1912-21
references.pmid: 18287530
references.citation: Lancet. 1970 Sep 12;2(7672):535-7
references.pmid: 4195202
references.citation: Biochem Biophys Res Commun. 2001 Dec 21;289(5):1287-94
references.pmid: 11741335
references.citation: Endocrinology. 2008 Jun;149(6):3196-205
references.pmid: 18325990
references.citation: Am J Clin Nutr. 1958 Sep-Oct;6(5):459-65
references.pmid: 13594869
references.citation: Am J Physiol Gastrointest Liver Physiol. 2009 Dec;297(6):G1193-7
references.pmid: 19779013
references.citation: Baillieres Clin Endocrinol Metab. 1997 Jul;11(2):341-65
references.pmid: 9403126
references.citation: Endocrinology. 2003 Sep;144(9):3885-94
references.pmid: 12933662
references.citation: Proc Natl Acad Sci U S A. 2005 Nov 29;102(48):17507-12
references.pmid: 16291808
references.citation: J Bone Miner Res. 2007 Feb;22(2):274-85
references.pmid: 17129178
references.citation: J Pediatr. 1992 Nov;121(5 Pt 1):803-8
references.pmid: 1331389
references.citation: Arch Biochem Biophys. 2005 May 1;437(1):51-8
references.pmid: 15820216
references.citation: J Bone Miner Res. 1987 Dec;2(6):595-610
references.pmid: 3455637
references.citation: Am J Physiol Gastrointest Liver Physiol. 2003 Jul;285(1):G78-85
references.pmid: 12620887
references.citation: Arch Biochem Biophys. 2003 Dec 1;420(1):194-200
references.pmid: 14622990
references.citation: Q J Med. 1975 Jul;44(175):505-21
references.pmid: 1178820
references.citation: Endocr Rev. 2008 Oct;29(6):726-76
references.pmid: 18694980
references.citation: J Bone Miner Res. 1988 Feb;3(1):37-45
references.pmid: 3264993
references.citation: Nat Genet. 1997 Aug;16(4):391-6
references.pmid: 9241280
references.citation: Cell Calcium. 2003 May-Jun;33(5-6):509-18
references.pmid: 12765696
references.citation: Am J Physiol. 1980 Nov;239(5):E322-7
references.pmid: 7435610
references.citation: J Clin Invest. 2006 May;116(5):1230-42
references.pmid: 16614757
references.citation: Arch Biochem Biophys. 2007 Apr 15;460(2):227-32
references.pmid: 17224126
references.citation: J Clin Invest. 1986 May;77(5):1661-7
references.pmid: 3009551
references.citation: J Endocrinol. 1989 Jan;120(1):143-51
references.pmid: 2783957
references.citation: J Am Soc Nephrol. 2003 Nov;14(11):2731-40
references.pmid: 14569082
references.citation: Am J Physiol Gastrointest Liver Physiol. 2001 Feb;280(2):G285-90
references.pmid: 11208552
references.citation: J Clin Invest. 1979 Sep;64(3):729-36
references.pmid: 468987
references.citation: Bone. 2003 Apr;32(4):332-40
references.pmid: 12689675
references.citation: J Bone Miner Res. 2000 Aug;15(8):1510-6
references.pmid: 10934649