Felix Bronner

Mechanisms of intestinal calcium absorption

Calcium is absorbed in the mammalian small intestine by two general mechanisms: a transcellular active transport process, located largely in the duodenum and upper jejunum; and a paracellular, passive process that functions throughout the length of the intestine. The transcellular process involves three major steps: entry across the brush border, mediated by a molecular structure termed CaT1, intracellular diffusion, mediated largely by the cytosolic calcium‐binding protein (calbindinD9k or CaBP); and extrusion, mediated largely by the CaATPase. Chyme travels down the intestinal lumen in ∼3 h, spending only minutes in the duodenum, but over 2 h in the distal half of the small intestine. When calcium intake is low, transcellular calcium transport accounts for a substantial fraction of the absorbed calcium. When calcium intake is high, transcellular transport accounts for only a minor portion of the absorbed calcium, because of the short sojourn time and because CaT1 and CaBP, both rate‐limiting, are downregulated when calcium intake is high. Biosynthesis of CaBP is fully and CaT1 function is approximately 90% vitamin D‐dependent. At high calcium intakes CaT1 and CaBP are downregulated because 1,25(OH)2D3, the active vitamin D metabolite, is downregulated. J. Cell. Biochem. 88: 387–393, 2003.

Studies in calcium metabolism; the fate of intravenously injected radiocalcium in human beings.

In the course of studies on the effect of phytates on calcium uptake in man (1) it became necessary to determine the extent to which endogenous calcium in the feces might contribute to the calcium balance. Although this point has been studied by several investigators (2-5), there is considerable disagreement on the significance of the fecal route for calcium excretion in man. Thus Malm (6) has observed that different individuals may exhibit pronounced variations in the fecal calcium excretion and has suggested that extended observations be made on each proposed test subject. Since this approach is not practicalin many cases, it seemed desirable to establish the significance of the endogenous calcium output in the feces under our experimental conditions.5 The method chosen for investigation was to inject radiocalcium (Ca45) intravenously and to determine its concentration in the serum, urine and feces during several days. Such studies have been

Recent developments in intestinal calcium absorption

Calcium absorption proceeds by transcellular and paracellular flux, with the latter accounting for most absorbed calcium when calcium intake is adequate. Vitamin D helps regulate transcellular calcium transport by increasing calcium uptake via a luminal calcium channel and by inducing the cytosolic calcium transporting protein, calbindinD(9k). Recent studies utilizing knockout mice have challenged the functional importance of the channel and calbindin. To integrate the new findings with many previous studies, the function of the two molecules must be evaluated in the calcium transport and economy of mice. When calcium intake is high, transcellular calcium transport contributes little to total calcium absorption. Therefore, increasing calcium intake seems the most effective nutritional approach to ensure adequate absorption and prevent bone loss.

Calcium Transport across Epithelia

Publisher Summary This chapter discusses mechanisms by which cells transport calcium and modify calcium fluxes in the body. The major chemical functions that are dependent on calcium include: nerve excitation, muscle contraction, extrusion, and export processes. The level and regulation of the calcium content of body fluids involves millimolar concentrations. Food calcium may undergo solubilization and dilution with bile and intestinal fluids; calcium concentrations in the chyme can reach tens of millimoles. Thus, the bodys calcium traffic—ingestion, digestion, absorption, plasma-calcium maintenance, cellular uptake and release, bone-calcium deposition and removal, i.e., resorption, urinary and fecal-calcium excretion—involves an unending manipulation of various calcium concentrations, as well as changes in state from liquid to solid and back to liquid. In the balance approach, the amount of calcium excreted in the stool is subtracted from the amount ingested during a comparable period. This is termed “net absorption.” The net amount of calcium absorbed represents the net load of calcium from the intestine. By using radioactive or stable isotopes of calcium, along with a balance procedure, one of the streams of calcium in the intestine can be labeled—either the endogenous or the food calcium—and thereby the true amount absorbed and the quantity of endogenous calcium lost in the stool can be quantitated.

Vitamin D-dependent calcium-binding protein from rat kidney

A calcium-binding protein has been partially purified from rat kidney. It is found in the cortex, but not in the medulla. It is Vitamin D-dependent, as it occurs in normal, but not in Vitamin D-deficient rats. The molecular weight is 28 000, more than twice that of the Vitamin D-dependent calcium-binding proteins from rat intestinal mucosa. The apparent dissociation constant of the partially purified renal calcium-binding protein is approx. 10-5 M.

Calcium-binding protein biosynthesis in the rat: Regulation by calcium and 1,25-dihydroxyvitamin D3

Abstract Vitamin D-replete rats on high or low calcium diets received by intraperitoneal injection varying doses (62.5–750 ng/animal) of 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 -D 3 ). The animals on the high calcium diet showed a progressive, dose-dependent response to the vitamin D metabolite; their duodenal levels of the cytosolic calcium-binding protein increased from about 50 nmol Ca bound /g mucosa to nearly 100 nmol Ca bound /g mucosa. The animals on the low calcium diet, whose calcium-binding protein base levels were about 100 nmol Ca bound /g mucosa, showed no response to the metabolite and their calcium-binding protein levels remained unchanged even with high doses of 1,25-(OH) 2 -D 3 . Vitamin D-deficient animals on a high calcium diet from weaning gave the same quantitative response to progressive doses of 1,25-(OH) 2 -D 3 as the replete animals, but the time and rate at which calcium-binding protein reached its maximum level in the intestine differed in the two groups. In the replete animals the calcium-binding protein response to 1,25-(OH) 2 -D 3 was completed by 1 h after treatment, whereas in the deficient rats the maximum response was not attained until 16–20 h. Plasma calcium responses to exogenous 1,25-(OH) 2 -D 3 occurred before the calcium-binding protein response in D-deficient animals and after in replete animals. The plasma calcium response therefore is not an index of the molecular response to vitamin D. It is concluded that the extent of the calcium-binding protein response to exogenous 1,25-(OH) 2 -D 3 is a function of the calcium status of the D-replete animal and that there exists an upper limit of this response. The time and rate of the calcium-binding protein response, on the other hand, depend on prior vitamin D status and may reflect a post-transcriptional as well as a transcriptional role of the metabolite in the intestinal cell.

Modulation of bone calcium-binding sites regulates plasma calcium: An hypothesis

SummaryA new model of calcium (Ca) homeostasis is proposed. It is based on the kinetics of restoration of the plasma Ca level following positive or negative Ca loads in animals of different endocrine status. As others, we can account for the kinetics of plasma Ca restoration as being the result of a very rapid dilution of Ca into extracellular water (t1/2<1 minute) and an uptake or release by bone (t1/2=14–80 minutes) that occurs as the fraction of cardiac output directed to bone is partially cleared of or repleted with Ca. In this model, bone surfaces have Ca-binding sites that demonstrate a range of affinities and whose average Km determines the plasma Ca level. Acute regulation is brought about by controlling access to subpopulations of Ca binding sites in bone, comprising the extremes of high and low affinity. Osteoblasts, when active and extended, block the low affinity sites, and osteoclasts, when active and extended, block the high affinity sites. Exposure of low- or high-affinity sites is brought about when these cells respond to hormonal signals by contraction, parathyroid hormone (PTH), and vitamin D leading to osteoblast, and calcitonin to osteoclast, contraction. These reciprocal cell shape changes are the first in a cascade of metabolic events that lead to bone formation and resorption, as well as changes in the number or affinity of the binding sites. The model also accounts for the prolongation of the response time to Ca loads in animals deprived of PTH, calcitonin, or vitamin D.

Extracellular and Intracellular Regulation of Calcium Homeostasis

An organism with an internal skeleton must accumulate calcium while maintaining body fluids at a well-regulated, constant calcium concentration. Neither calcium absorption nor excretion plays a significant regulatory role. Instead, isoionic calcium uptake and release by bone surfaces causes plasma calcium to be well regulated. Very rapid shape changes of osteoblasts and osteoclasts, in response to hormonal signals, modulate the available bone surfaces so that plasma calcium can increase when more low-affinity bone calcium binding sites are made available and can decrease when more high-affinity binding sites are exposed. The intracellular free calcium concentration of body cells is also regulated, but because cells are bathed by fluids with vastly higher calcium concentration, their major regulatory mechanism is severe entry restriction. All cells have a calcium-sensing receptor that modulates cell function via its response to extracellular calcium. In duodenal cells, the apical calcium entry structure functions as both transporter and a vitamin D–responsive channel. The channel upregulates calcium entry, with intracellular transport mediated by the mobile, vitamin D–dependent buffer, calbindin D9K, which binds and transports more than 90% of the transcellular calcium flux. Fixed intracellular calcium binding sites can, like the bodys skeleton, take up and release calcium that has entered the cell, but the principal regulatory tool of the cell is restricted entry.

A Model of the Kinetics of Lanthanum in Human Bone, Using Data Collected during the Clinical Development of the Phosphate Binder Lanthanum Carbonate

AbstractObjective: Lanthanum carbonate (Fosrenol®) is a non-calcium phosphate binder that controls hyperphosphataemia without increasing calcium intake above guideline targets. The biological fate and bone load of lanthanum were modelled with the aid of a four-compartment kinetic model, analogous to that of calcium. Methods: The model used data from healthy subjects who received intravenous lanthanum chloride or oral lanthanum carbonate, and bone lanthanum concentration data collected from dialysis patients during three long-term trials (up to 5 years). Results: Infusion of lanthanum chloride or ingestion of lanthanum carbonate led to a rapid rise in plasma lanthanum concentrations, followed by an exponential decrease. Comparison of oral and intravenous exposure confirmed that lanthanum is very poorly absorbed. On a typical intake of lanthanum (3000 mg/day as lanthanum carbonate), the rate of absorption was calculated as 2.2 μg/h, with a urinary excretion rate constant of 0.004—0.01 h−1. The faecal content of endogenous lanthanum was estimated to be 8- to 20-fold greater than that of urine, compared with a ratio of only about 1 for calcium. The model predicts that upon multiple dosing, plasma lanthanum concentrations rise rapidly to a near plateau and then increase by about 3% per year. However, this small change is obscured by the variability of the study data, which show that a plateau is rapidly attained by 2 weeks and is thereafter maintained for at least 2 years. The initial deposition rate of lanthanum in bone was 1 μg/g/year and, after 10 years of lanthanum carbonate treatment, the model predicts a 7-fold increase in total bone lanthanum (from 10 mg to 69 mg [from 1 μg/g wet weight to 6.6 μg/g wet weight]), with lanthanum cleared after cessation of treatment at 13% per year. The model indicates that lanthanum flow from bone surface to bone interior is much lower than that of calcium. Conclusion: Bone is the major reservoir for metals, but bone lanthanum concentrations are predicted to remain low after long-term treatment because of very poor intestinal absorption.

Compartmental analysis of calcium metabolism in very-low-birth-weight infants.

ABSTRACT: The calcium metabolism of 13 very-low-birth-weight infants fed a high-calcium diet was evaluated by means of stable isotope kinetic and balance studies. The studies used orally and i.v. administered stable isotopes, and the kinetic data were evaluated with the aid of a sequential, three-compartment model. The infants (postmenstrual age 33 ± 1 wk, weight 1.34 ± 0.03 kg) had higher bone calcium deposition rates (160 ± 7 mg·kg−1.d−1 or 4.00 ± 0.18 mmol·kg−1·d−1) than those previously reported for either older children or adults. Furthermore, when analyzed as a function of net calcium absorption, bone calcium deposition rates increased markedly and significantly as net calcium absorption increased (r = 0.70, p < 0.01), whereas in older individuals, bone calcium deposition is a relatively invariant function of absorption. A relatively smaller response of bone calcium removal to calcium absorption was found for the very-low-birth-weight infants in this study (r = −0.39, p = 0.18), whereas in adults, bone calcium removal constitutes the major regulatory response. It is suggested that the calcium kinetic results in the very-low-birth-weight infants reflect the high rate of bone growth typical of the third trimester of gestation.