Calcium is vital for many physiological functions including bone mineralization. Postnatal deposition of calcium into bone is greatest in infancy and continues through childhood and adolescence until peek mineral density is reached in early adulthood. Thereafter, bone mineral density remains static until it eventually declines in later life. A positive calcium balance, i.e. more calcium absorbed than excreted, is crucial to bone deposition during growth and thus to peek bone mineral density. Dietary calcium is absorbed from the intestine into the blood. It is then filtered by the renal glomerulus and either reabsorbed by the tubule or excreted in the urine. Calcium can be (re)absorbed across intestinal and renal epithelia via both transcellular and paracellular pathways. Current evidence suggests that significant intestinal and renal calcium transport changes occur throughout development. However, the molecular details of these alterations are incompletely delineated. Here we first briefly review the current model of calcium transport in the intestine and renal tubule in the adult. Then, we describe what is known with regard to calcium handling through postnatal development, and how alterations may aid in mediating a positive calcium balance. The role of transcellular and paracellular calcium transport pathways and the contribution of specific intestinal and tubular segments vary with age. However, the current literature highlights knowledge gaps in how specifically intestinal and renal calcium (re)absorption occurs early in postnatal development. Future research should clarify the specific changes in calcium transport throughout early postnatal development including mediators of these alterations enabling appropriate bone mineralization.
Impact statement
This mini review outlines the current state of knowledge pertaining to the molecules and mechanisms maintaining a positive calcium balance throughout postnatal development. This process is essential to achieving optimal bone mineral density in early adulthood, thereby lowering the lifetime risk of osteoporosis.
HoenderopJGJNiliusBBindelsRJM. Calcium absorption across epithelia. Physiol Rev2005; 85: 373–422.
2.
KopicSGeibelJP. Gastric acid, calcium absorption, and their impact on bone health. Physiol Rev2013; 93: 189–268.
3.
KovacsCS. Bone development and mineral homeostasis in the fetus and neonate: roles of the calciotropic and phosphotropic hormones. Physiol Rev2014; 94: 1143–218.
4.
BronnerFPansuD. Nutritional aspects of calcium absorption. J Nutr1999; 129: 9–12.
5.
GoldenNHAbramsSA. Optimizing bone health in children and adolescents. Pediatrics2014; 134: e1229–e43.
6.
Bachrach LK, Levine MA, Cowell CT, Shaw NJ. Clinical indications for the use of DXA in pediatrics. Bone densitometry in growing patients. Totowa, NJ: Springer, 2007, pp.59–72.
7.
KovacsCS. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol Rev2016; 96: 449–547.
8.
VeldurthyVWeiROzLDhawanPJeonYHChristakosS. Vitamin D, calcium homeostasis and aging. Bone Res2016; 4: 16041–16041.
9.
PeacockM. Calcium metabolism in health and disease. Clin J Am Soc Nephrol2010; 5: S23–30.
10.
BirgeSJPeckWABermanMWhedonGD. Study of calcium absorption in man: a kinetic analysis and physiologic model. J Clin Invest1969; 48: 1705–13.
11.
NormanDAFordtranJSBrinkleyLJZerwekhJENicarMJStrowigSMPakCYC. Jejunal and ileal adaptation to alterations in dietary calcium: changes in calcium and magnesium absorption and pathogenetic role of parathyroid hormone and 1,25-dihydroxyvitamin D. J Clin Invest1981; 67: 1599–603.
12.
SandstromBCederbiadAKivistooBStenquistBAnderssonH. Retention of zinc and calcium from the human coIon. Am J Clin Nutr1986; 44: 501–4.
13.
GrinsteadWCPakCYCKrejsGJ. Effect of 1,25-dihydroxyvitamin D3 on calcium absorption in the colon of healthy humans. Am J Physiol Gastrointest Liver Physiol1984; 247: G189–G92.
14.
AbramsSAEstebanNVVieiraNEYergeyAL. Calcium absorption and endogenous fecal excretion in low birth weight infants. Pediatr Res1991; 29: 615–8.
15.
HillmanLSJohnsonLSLeeDZVieiraNEYergeyAL. Measurement of true absorption, endogenous fecal excretion, urinary excretion, and retention of calcium in term infants by using a dual-tracer, stable-isotope method. J Pediatr1993; 123: 444–56.
16.
KarbachUSchmittASanerFH. Different mechanism of magnesium and calcium transport across rat duodenum. Dig Dis Sci1991; 36: 1611–8.
17.
KarbachU. Paracellular calcium transport across the small intestine. J Nutr1992; 122: 672–7.
18.
FavusMJ. Factors that influence absorption and secretion of calcium in the small intestine and colon. Am J Physiol1985; 248: G147–G57.
19.
NellansHNKimbergDV. Cellular and paracellular calcium transport in rat ileum: effects of dietary calcium. Am J Physiol Endocrinol Metab1978; 235: E726–E726.
20.
KarbachUFeldmeierH. The cecum is the site with the highest calcium absorption in rat intestine. Dig Dis Sci1993; 38: 1815–24.
21.
RievajJPanWCordatEAlexanderRT. The Na+/H+ exchanger isoform 3 is required for active paracellular and transcellular Ca2+ transport across murine cecum. Am J Physiol Gastrointest Liver Physiol2013; 305: G303–13.
22.
DuflosCBellatonCPansuDBronnerF. Calcium solubility, intestinal sojourn time and paracellular permeability codetermine passive calcium absorption in rats. J Nutr1995; 125: 2348–55.
23.
AlexanderRTRievajJDimkeH. Paracellular calcium transport across renal and intestinal epithelia. Biochem Cell Biol2014; 92: 467–80.
24.
LamerisALNevalainenPIReijnenDSimonsEEygensteynJMonnensLBindelsRJHoenderopJG. Segmental transport of Ca2+ and Mg2+ along the gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol2015; 308: G206–16.
25.
HoenderopJGHartogAStuiverMDoucetAWillemsPHBindelsRJ. Localization of the epithelial Ca2+ channel in rabbit kidney and intestine. J Am Soc Nephrol2000; 11: 1171–8.
26.
BiancoSDCPengJBTakanagaHSuzukiYCrescenziAKosCHZhuangLFreemanMRGouveiaCHAWuJ. Marked disturbance of calcium homeostasis in mice with targeted disruption of the Trpv6 calcium channel gene. J Bone Miner Res2007; 22: 274–85.
27.
BennBSAjibadeDPortaADhawanPHedigerMPengJ-BJiangYOhGTJeungE-BLiebenL. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. Endocrinology2008; 149: 3196–205.
28.
van der EerdenBCWeissgerberPFratzl-ZelmanNOlaussonJHoenderopJGSchreuders-KoedamMEijkenMRoschgerPde VriesTJChibaHKlaushoferKFlockerziVBindelsRJFreichelMvan LeeuwenJP. The transient receptor potential channel TRPV6 is dynamically expressed in bone cells but is not crucial for bone mineralization in mice. J Cell Physiol2012; 227: 1951–9.
29.
Woudenberg-VrenkenTELamerisALWeissgerberPOlaussonJFlockerziVBindelsRJFreichelMHoenderopJG. Functional TRPV6 channels are crucial for transepithelial Ca2+ absorption. Am J Physiol Gastrointest Liver Physiol2012; 303: G879–85.
30.
KellettGL. Alternative perspective on intestinal calcium absorption: proposed complementary actions of Cav1.3 and TRPV6. Nutr Rev2011; 69: 347–70.
31.
MorganELMaceOJHelliwellPAAffleckJKellettGL. A role for Cav1.3 in rat intestinal calcium absorption. Biochem Biophys Res Commun2003; 312: 487–93.
32.
Thongon N, Nakkrasae L-i, Thongbunchoo J, Krishnamra N, Charoenphandhu. Enhancement of calcium transport in Caco-2 monolayer through PKCzeta-dependent Cav1.3-mediated transcellular and rectifying paracellular pathways by prolactin. Am J Physiol Cell Physiol 2009;296:C1373-82.
33.
BronnerFPansuDSteinWD. An analysis of intestinal calcium transport across the rat intestine. Am J Physiol Gastrointest Liver Physiol1986; 250: G561–G9.
34.
BarleyNFRadhika PrathalingamSZhiPLegonSHowardAWaltersJRF. Factors involved in the duodenal expression of the human calbindin-D9k gene. Biochem J1999; 341: 491–500.
35.
AkhterSKutuzovaGDChristakosSDelucaHF. Calbindin D 9k is not required for 1,25-dihydroxyvitamin D3 -mediated Ca2+ absorption in small intestine. Arch Biochem Biophys2007; 460: 227–32.
36.
AlexanderRTBeggsMRZamaniRMarcussenNFrischeSDimkeH. Ultrastructural and immunohistochemical localization of plasma membrane Ca2+-ATPase 4 in Ca2+-transporting epithelia. Am J Physiol Renal Physiol2015; 309: F604–F16.
37.
RyanZCCraigTAFiloteoAGWestendorfJJCartwrightEJNeysesLStrehlerEEKumarR. Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D 3. Biochem Biophys Res Commun2015; 467: 152–6.
PanWBorovacJSpicerZHoenderopJGBindelsRJShullGEDoschakMRCordatEAlexanderRT. The epithelial sodium/proton exchanger, NHE3, is necessary for renal and intestinal calcium (re) absorption. Am J Physiol Renal Physiol2012; 302: F943–F56.
40.
FujitaHSugimotoKInatomiSMaedaTOsanaiMUchiyamaYYamamotoYWadaTKojimaTYokozakiH. Tight junction proteins claudin-2 and-12 are critical for vitamin D-dependent Ca2+ absorption between enterocytes. Mol Biol Cell2008; 19: 1912–21.
41.
LeiZMaedaTTamuraANakamuraTYamazakiYShiratoriHYashiroKTsukitaSHamadaH. EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. Dev Biol2012; 371: 136–45.
42.
HolmesJLVan ItallieCMRasmussenJEAndersonJM. Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Express Pattern2006; 6: 581–8.
43.
FujitaHChibaHYokozakiHSakaiNSugimotoKWadaTKojimaTYamashitaTSawadaN. Differential expression and subcellular localization of claudin-7,− 8,− 12,− 13, and− 15 along the mouse intestine. J Histochem Cytochem2006; 54: 933–44.
44.
LamerisALHuybersSKaukinenKMäkeläTHBindelsRJHoenderopJGNevalainenPI. Expression profiling of claudins in the human gastrointestinal tract in health and during inflammatory bowel disease. Scand J Gastroenterol2013; 48: 58–69.
45.
AmashehSMeiriNGitterAHSchönebergTMankertzJSchulzkeJDFrommM. Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells. J Cell Sci2002; 115: 4969–76.
46.
HwangIYangHKangHSAhnCHongEJAnBSJeungEB. Alteration of tight junction gene expression by calcium- and vitamin D-deficient diet in the duodenum of calbindin-null mice. Int J Mol Sci2013; 14: 22997–3010.
47.
AlevizakiCCIkkosDGSinghelakisP. Progressive decrease of true intestinal calcium absorption with age in normal man. J Nucl Med1973; 14: 760–2.
48.
PiyabhanPKrishnamraNLimlomwongseL. Changes in the regulation of calcium metabolism and bone calcium content during growth in the absence of endogenous prolactin and during hyperprolactinemia: a longitudinal study in male and female Wistar rats. Can J Physiol Pharmacol2000; 78: 757–65.
49.
KrishnamraNLotinunSLimlomwongseL. Acute effect and mechanism of action of prolactin on the in situ passive calcium absorption in rat. Bone Miner1993; 23: 253–66.
50.
PansuDBellatonCBronnerF. Developmental changes in the mechanisms of duodenal calcium transport in the rat. Am J Physiol1983; 244: G20–G6.
51.
ToverudSUDostalLA. Calcium absorption during development: experimental studies of the rat small intestine. J Pediatr Gastroenterol Nutr1986; 5: 688–95.
52.
ArmbrechtHJZenserTVBrunsMEDavisBB. Effect of age on intestinal calcium absorption and adaptation to dietary calcium. Am J Physiol Endocrinol Metab1979; 236: E769–E74.
53.
HorstRLDelucaHFJorgensenNA. The effect of age on calcium absorption and accumulation of 1,25-hydroxyvitamin D3 in intestinal mucosa of rats. Metab Bone Dis Relat Res1978; 1: 29–33.
54.
GhishanFKParkerPNicholsSHoyumpaA. Kinetics of intestinal calcium transport during maturation in rats. Pediatr Res1984; 18: 235–9.
55.
AmnattanakulSCharoenphandhuNLimlomwongseLKrishnamraNAmnattanakulSCharoenphandhuNLimlomwongseLKrishnamraN. Endogenous prolactin modulated the calcium absorption in the jejunum of suckling rats. J Physiol Pharmacol2005; 83: 595–604.
56.
SongYPengXPortaATakanagaHPengJ-BHedigerMAFleetJCChristakosS. Calcium transporter 1 and epithelial calcium channel messenger ribonucleic acid are differentially regulated by 1, 25 dihydroxyvitamin D3 in the intestine and kidney of mice. Endocrinology2003; 144: 3885–94.
57.
LeeG-SLeeK-YChoiK-CRyuY-HPaikSGOhGTJeungE-B. Phenotype of a calbindin-D9k gene knockout is compensated for by the induction of other calcium transporter genes in a mouse model. J Bone Miner Res2007; 22: 1968–78.
58.
ChristakosSDhawanPPortaAMadyLJSethT. Vitamin D and intestinal calcium absorption. Mol Cell Endocrinol2011; 347: 25–9.
59.
YoshizawaTHandaYUematsuYTakedaSSekineKYoshiharaYKawakamiTAriokaKSatoHUchiyamaYMasushigeSFukamizuAMatsumotoTKatoS. Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning. Nat Genet1997; 16: 391–6.
60.
Van CromphautSJDewerchinMHoenderopJGJStockmansIVan HerckEKatoSBindelsRJMCollenDCarmelietPBouillonR. Duodenal calcium absorption in vitamin D receptor–knockout mice: functional and molecular aspects. Proc Natl Acad Sci U S A2001; 98: 13324–9.
61.
DostalLAToverudSU. Effect of vitamin D3 on duodenal calcium absorption in vivo during early development. Am J Physiol Gastrointest Liver Physiol1984; 246: G528–G34.
62.
HalloranBPDeLucaHF. Calcium transport in small intestine during pregnancy and lactation. Am J Physiol Endocrinol Metab1980; 239: E64–E8.
63.
AllenLH. Calcium bioavailability and absorption: a review. Am J Clin Nutr1982; 35: 783–808.
64.
SatoRNoguchiTNaitoH. Effect of lactose on calcium absorption from the rat small intestine with a non-flushed ligated loop. J Nutr Sci Vitaminol (Tokyo)1983; 29: 365–73.
65.
SongYKatoSFleetJC. Vitamin D receptor (VDR) knockout mice reveal VDR-independent regulation of intestinal calcium absorption and ECaC2 and calbindin D9k mRNA. J Nutr2003; 133: 374–80.
66.
CoxDBOwensRAHartmannPE. Blood and milk prolactin and the rate of milk synthesis in women. Exp Physiol1996; 81: 1007–20.
FreemanMEKanyicskaBLerantANagyG. Prolactin: structure, function, and regulation of secretion. Physiol Rev2000; 80: 1523–631.
69.
NaganoMChastreEChoquetABaraJGespachCKellyPA. Expression of prolactin and growth hormone receptor genes and their isoforms in the gastrointestinal tract. Am J Physiol1995; 268: G431–42.
70.
WongdeeKTeerapornpuntakitJSripongCLongkunanAChankamngoenWKeadsaiCKraidithKKrishnamraNCharoenphandhuN. Intestinal mucosal changes and upregulated calcium transporter and FGF-23 expression during lactation: contribution of lactogenic hormone prolactin. Arch Biochem Biophys2016; 590: 109–17.
71.
DorkkamNWongdeeKSuntornsaratoonPKrishnamraNCharoenphandhuN. Prolactin stimulates the L-type calcium channel-mediated transepithelial calcium transport in the duodenum of male rats. Biochem Biophys Res Commun2013; 430: 711–6.
72.
DimkeHHoenderopJGJBindelsRJM. Molecular basis of epithelial Ca2+ and Mg2+ transport: insights from the TRP channel family. J Physiol2011; 589: 1535–42.
73.
DimkeHHoenderopJGBindelsRJ. Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+. Clin Sci (Lond)2010; 118: 1–18.
74.
HoenderopJGMüllerDVan Der KempAWHartogASuzukiMIshibashiKImaiMSweepFWillemsPHVan OsCHBindelsRJ. Calcitriol controls the epithelial calcium channel in kidney. J Am Soc Nephrol2001; 12: 1342–9.
Hoenderop JGJ, van Leeuwen JPTM, van der Eerden BCJ, Kersten FFJ, WCM van derKemp A, Mérillat A-M, Waarsing JH, Rossier BC, Vallon V, Hummler E. Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 2003;112:1906-14.
77.
GkikaDHsuY-JVan Der KempAWChristakosSBindelsRJHoenderopJG. Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/Calbindin-D 28K knockout mice. J Am Soc Nephrol2006; 17: 3020–7.
78.
ZhengWXieYLiGKongJFengJQLiYC. Critical role of calbindin-D28k in calcium homeostasis revealed by mice lacking both vitamin D receptor and calbindin-D28k. J Biol Chem2004; 279: 52406–13.
79.
van LoonEPMLittleRPreharSBindelsRJMCartwrightEJHoenderopJGJ. Calcium extrusion pump PMCA4: a new player in renal calcium handling?PLoS One2016; 11: e0153483–e0153483.
80.
KoushikSVWangJRogersRMoskophidisDLambertNACreazzoTLConwaySJ. Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J2001; 15: 1209–11.
81.
BindelsRJRamakersPLDempsterJAHartogAvan OsCH. Role of Na+/Ca2+ exchange in transcellular Ca2+ transport across primary cultures of rabbit kidney collecting system. Pflugers Archiv1992; 420: 566–72.
82.
Muto S, Hata M, Taniguchi J, Tsuruoka S, Moriwaki K, Saitou M, Furuse K, Sasaki H, Fujimura A, Imai M, Kusano E, Tsukita S, Furuse M, Giebisch G, Muto3 ‘ S, Hatab M, Taniguchic J, Tsuruokad S, Moriwaki6 K, Saitouf M, Furuseb K, Sasaki6 H, Fujimurad A, Lmaicf M, Kusanoaf E, Tsukitaf S, Furuse M, Giebisch. Claudin-2 – deficient mice are defective in the leaky and cation-selective paracellular permeability properties of renal proximal tubules. Proc Natl Acad Sci U S A 2010;107:8011-6.
83.
SchnermannJHuangYMizelD. Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Renal Physiol2013; 305: F1352–64.
84.
HouJReniguntaAGomesASHouMPaulDLWaldeggerSGoodenoughDA. Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. Proc Natl Acad Sci U S A2009; 106: 15350–5.
85.
DimkeHDesaiPBorovacJLauAPanWAlexanderRT. Activation of the Ca2+-sensing receptor increases renal claudin-14 expression and urinary Ca2+ excretion. Am J Physiol Renal Physiol2013; 304: F761–F9.
86.
GongYReniguntaVHimmerkusNZhangJReniguntaABleichMHouJ. Claudin-14 regulates renal Ca++ transport in response to CaSR signalling via a novel microRNA pathway. EMBO J2012; 31: 1999–2012.
87.
PlainAWulfmeyerVCMilatzSKlietzAHouJBleichMHimmerkusN. Corticomedullary difference in the effects of dietary Ca2+ on tight junction properties in thick ascending limbs of Henle’s loop. Pflügers Archiv2016; 468: 293–303.
88.
GongYHimmerkusNPlainABleichMHouJ. Epigenetic regulation of microRNAs controlling CLDN14 expression as a mechanism for renal calcium handling. J Am Soc Nephrol2015; 26: 663–76.
89.
RiccardiDValentiG. Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol2016; 12: 414–25.
90.
MayrBSchnabelDDorrHGSchoflC. Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts. Eur J Endocrinol2016; 174: R189–208.
91.
JacintoJSModanlouHDCradeMStraussAABosuSK. Renal calcification incidence in very low birth weight infants. Pediatrics1998; 81: 31–5.
92.
MatosVvan MelleGBoulatOMarkertMBachmannCGuignardJ-P. Urinary phosphate/creatinine, calcium/creatinine, and magnesium/creatinine ratios in a healthy pediatric population. J Pediatr1997; 131: 252–7.
93.
EsbjornerEJonesI. Urinary calcium excretion in Swedish children. Acta Paediatr1995; 84: 156–9.
94.
AbuazzaGBeckerAWilliamsSSChakravartySTruongH-TLinFBaumM. Claudins 6, 9, and 13 are developmentally expressed renal tight junction proteins. Am J Physiol Renal Physiol2006; 291: F1132–41.
95.
van AbelMHuybersSHoenderopJGJvan der KempAWCMvan LeeuwenJPTMBindelsRJM. Age-dependent alterations in Ca2+ homeostasis: role of TRPV5 and TRPV6. Am J Physiol Renal Physiol2006; 291: F1177–F83.
96.
ChengZLiangNChenT-HLiASanta MariaCYouMHoHSongFBikleDTuCShobackDChangW. Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice. J Bone Miner Res2013; 28: 1087–100.
97.
SasDHuMMoeOWBaumM. Effect of claudins 6 and 9 on paracellular permeability in MDCK II cells. Am J Physiol Regul Integr Comp Physiol2008; 295: R1713–9.
