©2013 Poultry Science Association, Inc.

Calcium and phosphorus metabolism in

broilers: Effect of homeostatic mechanism on
1
calcium and phosphorus digestibility
Monika Proszkowiec-Weglarz and Roselina Angel2

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University of Maryland, Department of Animal and Avian Sciences,
Building 142, Room 4131, College Park 20742

Primary Audience: Nutritionists, Researchers

SUMMARY
In this paper, we present a review of the current knowledge of calcium and phosphorus
metabolism as it relates to homeostatic mechanisms in poultry; contrasts with mammalian sys-
tems, as well as information that is available for mammalian systems but not for avian systems, are
included. The importance of understanding these homeostatic mechanisms and their effect on Ca
and P absorption are discussed briefly in the context of correctly formulating poultry diets. Clearly
deficiencies, excesses, or imbalances in Ca and P result in a cascade of changes, including
increases or decreases in the absorption of these 2 minerals from the intestinal lumen. The effect of
these changes on the actual digestibility of Ca and P from ingredients or diets has not been
determined yet; most of the methodologies we used for the determination of P digest-ibility are
done under deficient conditions. The methods used to determine the release of Ca and P from diets
when phytases were used were also done under deficient Ca and P conditions. given the effect of
Ca and P homeostatic mechanisms on absorption, methodologies and, pos-sibly, the quantitative
the effect of these homeostatic mechanisms on values generated for Ca and P should be reviewed
before they can confidently be applied.

Key words: calcium, phosphorus, parathyroid hormone, vitamin d, metabolism, transporter, broiler
2013 J. Appl. Poult. Res. 22:609–627
http://dx.doi.org/10.3382/japr.2012-00743
INTRODUCTION and within cells, and plays pivotal roles in me-

Calcium and phosphorus are essential nu-
trients involved in many biological processes.
These minerals are the most abundant ele-
ments in the body, with 99% of Ca and 80%
of P stored in the skeleton as hydroxyapatite,
and both play an important role in bone devel-
opment and mineralization [1]. The remaining
Ca is located in the extracellular fluid, plasma,
tabolism, blood clotting, enzyme activation,
neuromuscular function, muscle contraction,
cell adhesion, and intracellular signaling [1].
Nucleic acids, nucleotides, phospholipids, and
phosphorylated proteins play a fundamental
role in growth, cellular and membrane function,
energy metabolism, and acid-base balance, and
are the main location of the 20% of P not lo-
cated in the skeleton [1–3].

1
Presented as a part of the Informal Nutrition Symposium “Metabolic Responses to Nutrition and Modifiers” at the Poultry
Science Association’s annual meeting in Athens, georgia, July 9, 2012.
2 Corresponding author: rangel@umd.edu
610
The growth rate of the chicken has increased in
recent decades [4]; according to the Nation-al
Chicken Council [5], in 1925 the average chicken
weight was approximately 1.13 kg and required
112 d to achieve this weight. By 1980, the average
broiler weight was 1.78 kg at 53 d; in 2011, only
47 d were needed for broilers to achieve 2.63 kg.
These gains in production ef-ficiency were
coupled with decreased mortal-ity, going from 18
to 5 to 3.8%, in 1925, 1980, and 2011,
respectively [5]. Such rapid growth requires
adequate nutritional supply and, in the case of
rapid bone growth, adequate Ca and P supply [6].
Insufficient supply of one or both minerals, when
the deficiency or excess of one of them interferes
with homeostasis of the sec-ond one [7], results in
reduced growth rate and bone mineralization [8,
9]. Moreover, Ca and P deficiencies in fast-
growing broiler lines can lead to skeletal
abnormalities, such as rickets and tibial
dyschondroplasia, which lead to lame-ness and
increased morbidity and mortality [6, 10–12]. The
level of mortality due to the skeletal disorders has
been estimated to be approximate-ly 3% in the
United States [13], which is 60% of total
mortality reported in the broiler industry by the
NRC [5]. Imbalances in dietary Ca and P can also
result in excess amounts of P excretion that can
have negative environmental effects when poultry
litter is applied as a fertilizer to soil, causing
eutrophication and environmental pollution [14].
To minimize dietary P concentrations, it is
critical to formulate diets at correct Ca to P ra-
tios. To implement correct Ca to P ratios in diets it
is essential that we know the digestibility of Ca
and P in the ingredients that we use for poul-try,
and what the requirements are expressed as in
digestible terms. Recently, a move toward the use
of digestible P (dP) has been noted [15, 16], but
total Ca (tCa) continues to be the standard. This
means the issue of low P availability from plant
sources and overall availability of total P (tP) has
been partially addressed, but the issue of Ca
availability in the ingredients has not been
addressed.
The use of a tCa to tP ratio system [17] has
changed to a tCa to inorganic P ratio [18] to the
use of the tCa to available P (aP) ratio that ap-
peared in the 1984 NRC [19]. In 1950, the re-
quirements were 1.0% tCa and 0.6% tP (1.66
JAPR: Symposium
tCa:tP) [17] and, in 1954 [18], the qualification
was made to give importance to the availability of
P by specifying that, of the 0.6% tP require-ment,
0.56% needed to be from an inorganic source. An
allowance of 0.3% availability of plant P was
given. The 1977 NRC [20] still used tCa and tP in
the requirement tables, leaving the proviso that
part of the 0.7% tP requirement for P from 0 to 8
wk be supplied from inorganic sources of P. In the
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1984 NRC [19], aP values were given for
requirements as well as for ingre-dients, and the
Ca:aP ratios recommended were 2.22 to 2.28 Ca
to 1 P throughout growth. By 1994 [21], the term
nonphytin P (nPP) was used instead of aP, but
values did not change, and the recommended Ca
to nPP ratios were 2.22 to 2.67 Ca to 1 nPP
depending on growth stage.
The low digestibility of P in plant sources [22–
24] prompted the change in the use of P, from
total to aP, nPP, and dP that better reflected
availability of P in dietary sources. However,
there has been no move toward a digestible Ca
(dCa) system. Because of the extensive use of
phytases in poultry diets worldwide and the
negative effect of Ca on phytate P digestibility
[23, 24] and on phytase efficacy [25], a reduc-tion
in the use of Ca in poultry diets has been
observed. Because there is very little data on the
actual availability or digestibility, as opposed to
relative availability, of calcium in feed ingredi-ent
sources, we assume a 100% digestibility for Ca,
in general. Clearly this is not correct; based on
reported Ca digestibilities in corn-soy diets with
no added inorganic Ca or P sources and the same
diet with added limestone, one can calcu-late an
availability of Ca in corn and soy of 20 to 30%
[23, 25] and for Ca from limestone of between 60
and 70%. The Ca from corn and soy in a corn-soy
diet represents between 0.17 and 0.21%. This low
digestibility of this Ca has been disregarded up to
now because it represents a small (20%)
percentage in a diet typical of a broiler starter diet
containing 1% Ca. However, when using diets
with 0.6% Ca becomes more widespread, then Ca
from the corn and soy be-comes a greater
proportion of total Ca.
It is important to start developing a dCa to dP
system if broilers are to be fed at a requirement
concentration. For this, methodologies to deter-
mine dCa in ingredients need to be developed and
methodologies used to determine dP and ex-
Proszkowiec-Weglarz and Angel: INFORMAL NUTRITION SYMPOSIUM
pected contributions of P and Ca when phytases
are used need to be reviewed. Most current sys-
tems determine digestibilities with all or part of
the diets being deficient [22, 26]. The first step
is to review what is known about Ca and P me-
tabolism and how Ca- and or P-deficient diets
effect Ca and P digestibilities. In this review,
we discuss what we know about Ca and P
metabo-lism and homeostasis in broilers
chicken and suggest areas where we still do not
have enough information for chicken.
CALCIUM AND PHOSPHORUS
METABOLISM
Plasma Ca and P concentrations are con-
trolled within a narrow physiological range
through feedback mechanisms consisting of
parathyroid hormone (PTH), active vitamin D3
[1,25-dihydroxyvitamin D3; 1,25(OH)2D3], cal-
citonin (CT), and their respective receptors lo-
calized in the small intestine, bone, and kidneys
[1].
Calcium Homeostasis
Plasma total and ionized Ca concentrations
in growing chicken are similar to those
observed in mammals (10 mg/dL, 1.2–1.3
mmol, respec-tively) [27].
Vitamin D3. Vitamin D3 can be synthesized
from isomerization of 7-dehydrocholesterol to
vitamin D3 in the skin after exposure to UV light
or from natural or supplemental vitamin D2 or D3
in the diet [28]. Vitamin D3 has 10 times higher
biological activity than vitamin D2 in birds [29].
Once vitamin D3 is formed in the skin, it binds to
a vitamin D-binding protein and is stored in this
form in fat or transported to the liver [30]. To
become active, vitamin D2 or D3 must undergo a
double hydroxylation reaction
[28]. The first hydroxylation, resulting from the
action of 25-hydroxylase, takes place mainly in
the liver and results in the formation of 25-hy-
droxy D3 (25(OH)D3). The second hydroxyl-ation
and the formation of the active form of vitamin
D3, 1,25(OH)2D3, occurs in the kidneys and is
facilitated by 1α-hydroxylase [31]. The
fundamental role of 1,25(OH) 2D3 in vertebrates is
to control Ca and P homeostasis though direct
actions of the hormone (1,25(OH)2D3) on the in-
611
testine, kidney, and bones and through feedback
inhibition of PTH production in the parathyroid
glands [32]. Activation of vitamin D 3 depends on
plasma Ca concentrations; if the Ca concen-
tration is low, renal 1α-hydroxylase is activated
and 1,25(OH)2D3, the active form of vitamin D 3,
is synthesized. If the Ca concentration is ade-
quate, 25(OH)D3 undergoes 24-hydroxylation to
the inactive metabolite 25,24(OH)2D3 in the kid-
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ney [31]. The 1,25(OH)2D3 also controls its own
production by inhibiting renal 1α-hydroxylase and
stimulating 24-hydroxylase [28]. Addition-ally,
renal 1α-hydroxylase is also regulated by PTH
and CT [33–35].
The physiological role of vitamin D in Ca
homeostasis in chicken has been studied ex-
tensively. Gonermna et al. [36] indicated that
vitamin D is important for Ca homeostasis and
responsiveness to PTH in chicken. Lack of vi-
tamin D impairs the Ca-mobilizing response to
PTH injections [36], resulting in the chicken not
being able to maintain a normal plasma Ca
concentration [37]. Those chicks that were not
able to respond to a moderate dose of PTH are
characterized by decreased plasma Ca and bone
ash [38]. Addition of Ca into a vitamin D-de-
ficient diet (2.8% Ca) for 14, 17, and 21 d led to
increased plasma Ca and bone ash in leghorn
chickens [36]. It has been shown that vitamin D
deficiency decreases the concentration of re-nal
PTH receptor and its activity [39]. Further-more,
Russell et al. [40] demonstrated a definite
interaction between Ca and 1,25(OH)2D3 in the
regulation of parathyroid gland function. They
reported that Ca and 1,25(OH)2D3 can regulate
PTH and vitamin D receptor (VDR) mRNA ex-
pression in chicken parathyroid glands. A high
dietary Ca (1.8%) in vitamin D-deficient chick-
ens led to increased plasma Ca concentration as
well as an increase in VDR mRNA expression in
parathyroid gland, whereas mRNA concentra-tion
of PTH was reduced [40]. Treatment with
1,25(OH)2D3 (2 µg/kg) resulted in an increase in
VDR mRNA concentration and a decrease in pre-
pro-PTH mRNA expression in parathyroid glands
in chicken. This change was potentiated by high
doses of 1,25(OH)2D3 (10 µg/kg) in the presence
of high dietary Ca (1.9%) concentra-tions [40].
The 1,25(OH)2D3 has been shown to stimu-
45
late Ca uptake in perfused chicken duodenum
612
[41–43]. Furthermore, Bar et al. [44] reported that
fast-growing chickens (Cobb) fed a Ca- and P-
restricted diet from hatch to 11 d of age, were
characterized by slight hypocalcemia, increased
renal 1α-hydroxylase activity and duodenal cal-
bindin D28k concentration, and a decrease in bone
ash in the case of Ca restriction (0.19% Ca).
Based on the work of Henry et al. [45], it is
possible that both 24,25(OH) 2D3 and
1,25(OH)2D3 are required for normal chick-en
hatchability. When hens were raised on
1,25(OH)2D3 as the only source of cholecalcif-
erol, they laid fertile eggs that developed nor-
mally but failed to hatch. In contrast, when hens
received 1,25(OH)2D3 and 24,25(OH) 2D3, their
eggs developed and hatched normally [45]. Ne-
mere [43] reported that 24,25(OH)2D3 has the
ability to decrease or eliminate the stimulatory
effects of 1,25(OH)2D 3 and PTH on Ca transport
in the perfused duodenal loop system in leghorn
chicks.
VDR. Similar to mammals, the presence of
VDR has been documented in various chicken
tissues, including the intestine, kidney, bone, and
parathyroid gland [29, 42, 46, 47]. Chicken
homolog of VDR and its promoter have been
cloned and characterized recently [48, 49].
Chicken VDR shared low homology with mam-
malian counterparts in the case of the first 3 ex-
ons, but homology of the coding sequence start-
ing from exon 4 was highly conserved between
avian and mammalian species [49]. Vitamin D
receptor mRNA was not affected by the pres-ence
or absence of dietary vitamin D, whereas low
dietary Ca results in a VDR mRNA decrease in
chickens [50]. According to a genomic gener-al
model of 1,25(OH)2D3 mechanism of action, after
diffusion into cells the hormone interacts with
either cytoplasmic or nuclear VDR, form-ing
heterodimers with retinoid X receptor that bind to
a specific DNA sequence (vitamin D re-sponse
element; VDRE) in the promoter region of target
genes. Vitamin D receptor and retinoid X receptor
interaction with VDRE is followed by the
recruitment of a series of coregulatory complexes
that lead, in turn, to changes in the transcriptional
output of targeted genes [32]. Functional VDRE
have been discovered and de-scribed in the
promoter region of many genes in vertebrates,
including 25(OH)D3 24-hydroxy-lase, PTH, PTH-
related proteins, calbindin D9k
JAPR: Symposium
and D28k, calcium ion channel, osteocalcin, or
osteoportin [32, 49, 51]. Most of the action of vi-
tamin D is carried out through the genomic path-
way involving VDR as described above. How-
ever, rapid responses to 1,25(OH)2D3, which
cannot be attributed to the mechanism described
(including Ca uptake from intestine), have been
characterized recently. These responses are very
quick (minutes to hours) and cannot be gener-ated
via the relatively slow (hours to days) ge-nomic
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pathways [52]. A binding protein with the
capability to bind 1,25(OH)2D3 that is not related
to the classic VDR has been identified in the
chicken intestinal basal lateral membrane [42,
46]. Huhtakangas et al. [52] provided evi-dence of
a close association between VDR and caveolae-
enriched plasma membranes that can bind
1,25(OH)2D3 with high affinity in vivo and in
vitro in various mammalian and avian tissues,
including the intestinal mucosa and kidney. Quick
activation of protein kinase C (PKC) and A
(PKA) within a couple of minutes is observed
when isolated intestinal cells are incubated with
1,25(OH)2D 3 (130 pM), whereas rapid activa-tion
of only PKA is observed during incubation with
bovine PTH [43].
PTH. Parathyroid hormone is synthesized in
the chief cells of the parathyroid glands as a
prepro-peptide containing a 25-amino acid pre-
sequence (signal sequence) and a 6-amino acid
prosequence [53]. Both are cleaved off before the
mature full-length PTH, composed of 84 amino
acids, is formed (PTH(1–84)) [53]. The action of
PTH is initiated by its binding to the PTH mem-
brane receptor [54]. Under physiological con-
ditions, PTH is released in response to low Ca
concentration predominantly as the PTH(1–84)
molecule [55]. The short form of PTH, com-posed
of first 34 amino acids (PTH(1–34)) of PTH(1–
84), is the native bioactive circulating form of
PTH [56]. Parathyroid hormore responds to acute,
short-term changes in Ca concentration as well as
to sustained low Ca concentration. In the case of
sustained low Ca concentration, PTH stimulates
the conversion of vitamin D3 to 1,25(OH)2D3
that, in turn, increases intestinal Ca absorption
[57, 58] via a dual mechanism involv-ing PKA-
and PKC-dependent pathways [59, 60]. Activation
of both protein kinase pathways by PTH also
leads to an increase in Ca reabsorp-tion from
renal tubes [61].
Proszkowiec-Weglarz and Angel: INFORMAL NUTRITION SYMPOSIUM
Chicken pre-proPTH was cloned and charac-
terized by Russell and Sherwood [62, 63]. They
found that the chicken mRNA homolog of PTH
was 3 times larger than the mammalian mRNA
[62–64]. The coding sequence consists of 357
nucleotides that code for chicken PTH protein
made up of 88 amino acids—4 amino acids longer
then the mammalian hormones [64]. As in
mammals, the reduced hormone sequence is
characterized by the presence of a 25 amino acid
leader sequence followed by prohormone hexa-
peptide. The biologically active region (amino
acids 1–34) showed 56 to 65% homology with the
mammalian hormone [62]. It has been shown that
partially purified chicken PTH can dramati-cally
stimulate cyclic adenosine monophosphate
production in disperse bovine and chicken kid-ney
cells [65, 66]. Moreover, based on com-parisons
of biological potencies of chicken PTH(1–34)
with human PTH(1–34) and chick-en PTH(1–88)
in mammalian and chicken cells, chicken PTH has
markedly diminished potency in mammalian cell
lines; but both chicken forms of PTH, (1–34) and
(1–88), are equally active in chicken kidney cells
[67]. Nemere and Norman
[41] reported that PTH has a direct effect on in-
testinal Ca transport. Furthermore, an increased
size and metabolic activity of the parathyroid
gland was observed in vitamin D-deficient chicks
in response to hypocalcemia [68], where-as
increased Ca concentration has been shown to
decrease PTH secretion [69]. Identification of
VDRE in the promoter region of the PTH gene
[51] suggests that, as in mammals, chicken PTH
gene expression could be regulated by vitamin D.
Vitamin D response element has been shown to be
involved in the inhibitory effect of the ac-tive
vitamin D3 on PTH gene transcription in chickens
[51]. The presence of a functional PTH receptor
in chicken tissues, including the kidney and
duodenum, has been documented [70].
Ca-Sensing Receptor. Parathyroid chief cells
sense high Ca concentration through the Ca-
sensing receptor (CaR) [57, 71]. Activa-tion of
the CaR in the parathyroid gland by Ca stimulates
the release of intracellular Ca and ac-tivates Ca-
dependent proteases that cleave and inactivate
PTH [53]. The chicken homolog of CaR has been
cloned, and in situ hybridization revealed that
CaR is present in the parathyroid, kidney, and
duodenum [27]; chicken and human
613
CaR share 79 and 84% homology on the nucleo-
tide and amino acid level, respectively [27].
Yarden et al. [72] showed that the CaR protein is
expressed in the chief cells of the parathyroid
gland, the same cells that store PTH in chick-ens.
It has also been determined that expression of
CaR within the parathyroid gland is affected by
dietary vitamin D3 deficiency and plasma Ca
concentration. Yarden et al. [60] reported that the
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lowest level of CaR expression was observed in
chickens fed a vitamin D-deficient diet (1% Ca,
0.72% P, and no vitamin D) and resulted in lower
concentration of plasma Ca as compared with
chicks fed a diet containing vitamin D. Maximal
expression of CaR was ob-served in broiler
chickens with a high plasma Ca concentration
after diet repletion with vitamin D or injection of
PTH [72]. In contrast to rats [73, 74], elevated Ca
plasma concentration was shown to induce CaR
gene expression in chick-ens [72]. An inverse
relationship between CaR expression and PTH
content within the parathy-roid gland was shown
in chickens [72]. Vitamin D-deficient chickens
with low CaR expression were characterized by
the highest concentra-tion of PTH, whereas high
CaR gene expression level in vitamin D-depleted
chickens was asso-ciated with low PTH content in
the parathyroid gland [72]. All these data indicate
the presence of a functional CaR in the chicken
with similar characteristics as its mammalian
counterparts.
CT. Calcitonin is a 32 amino acid peptide se-
creted from thyroid glands in response to a high
plasma Ca concentration and its expression is
regulated by 1,25(OH)2D3 [75–79]. Calcitonin
functions also as an inhibitor of bone resorption,
thus leading to a decreased plasma Ca concen-
tration [80]. It has been shown that chickens fed a
Ca-deficient diet had lower plasma Ca and CT
concentration in comparison to chickens fed an
adequate-Ca diet [81].
Ca Transport. Intestinal Ca can be transport-
ed through active (saturable) and passive (un-
saturable) transport. A transcellular, active, and
metabolically driven transport involves 3 steps:
entry across the cell wall, diffusion through the
cytoplasm, and exit at the basolateral cell mem-
brane. Passive transport, conversely, is char-
acterized by ion movement from the intestinal
lumen to the circulation along the chemical
gradient through spaces between cells [82–84].
614
When Ca intake is either high or at adequate
concentrations, passive transport of Ca predom-
inates due to inhibition of active Ca transport
by high plasma Ca concentrations [85]. Passive
transport of Ca occurs throughout the length of
the small intestine [85] and does not seem to be
dependent on vitamin D [74]. However, reports
supporting its vitamin D-dependency are con-
tradictory [86]. In contrast to passive transport,
active Ca transport has been associated with the
upper duodenum [87] and is vitamin D-depen-
dent [87]. Active intestinal absorption can be
regulated by dietary Ca concentration; low di-
etary Ca or increased Ca needs increased active
absorption of Ca [83, 88].
The first step of the active intestinal Ca trans-
port—entry across the cell wall—is facilitated by
2 epithelial Ca selective anion channels [89, 90]
that belong to the super family of tran-sient
receptor potential channels (TRPV5 and TRPV6)
[91]. Both channels are expressed in several
tissues, including the intestine, where they are
localized on the brush border membrane [89, 92].
It has been suggested that both chan-nels form the
rate-limiting step in transcellular Ca absorption
[93] in the kidney and intestine [93–95]. Based on
quantitative PCR and im-munohistochemical
analysis, both channels are expressed in intestinal
tissues; however, TRPV6 is expressed at a much
higher level [96, 97]. In the intestine, the highest
expression of TRPV6 is in duodenum and ceca,
followed by the colon, and is lowest in the ileum;
whereas TRPV5 is predominantly expressed in
kidney, with limited expression in duodenum and
ceca [98]. Cal-cium transporters have been well
characterized in laying birds [99, 100]; however,
the specific role of TRPV in the transport of Ca
across the brush border membrane in the intestine
has not yet been characterized in laying hens [99]
or in broiler tissues. We were not able to detect
the presence of TRPV6 transcript in chicken duo-
denal mucosa (Figure 1) using real time-PCR and
primers designed based on the predicted sequence
for chicken homolog of mammalian TRPV6
(GenBank Accession #XM_416530; unpublished
data). Gene coding for TRPV5 in chicken or other
avian species has not yet been identified. Further
studies are required to iden-tify and characterize
the chicken homolog of
JAPR: Symposium
Figure 1. Expression of transient receptor potential
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channel 6 (TRPV6), calbindin D28k, vitamin D recep-tor
(VDR), plasma membrane calcium pump (PMCA), and
Na-P cotransporter IIb (Na/PIIb) mRNA in chicken
duodenal mucosa from 10-d-old broiler chickens. Real-
time PCR and gene-specific primers were used to de-
termine the presence of mRNA for chosen genes. A
typical separation of real-time PCR product on 1.5%
agarose gel stained with ethidium bromide is shown.
TRPV5 and TRPV6 and determine their role in
the Ca transport in chicken.
Calbindin D9k and D28k are responsible for
transcellular diffusion of Ca in the mammalian
intestine and renal tissue, respectively. They bind
Ca and move it from the brush border mem-brane
to the basolateral membrane of duodenal cell
[101, 102]. A vitamin D-induced calbindin D 28k
has been identified in chickens by Wasser-man
and Taylor [103] and, in contrast to that in
mammals, is the primary protein responsible for
transcellular diffusion of Ca in avian intestine. In
contrast to mammals, avian intestinal and re-nal
calbindin D are identical and have the same
molecular weight, immunogenicity, and amino
acid sequence [104–106]. Moreover, in the avi-an
intestine and kidney there are 3 variants of mRNA
that encode a major (2 kb) and 2 minor transcripts
(2.7 and 3 kb), but all of them code
for the same calbindin D28k [99]. The role of cal-
bindin D28k in Ca absorption has been studied
extensively in birds. It was believed that stimu-
lation of Ca absorption requires the following
sequence of events: active vitamin D synthe-sis,
an increase in gene expression of intestinal
transporters, and an increase in calbindin D28k
synthesis in the intestine followed by increase in
Ca absorption. However, Spencer et al. [107]
suggested that synthesis of the calbindin D28k
protein in the chicken intestine is a consequence
of 1,25(OH)2D3-stimulated Ca absorption rather
than the mediator of this process. Moreover, these
authors found that intestinal calbindin D28k
Proszkowiec-Weglarz and Angel: INFORMAL NUTRITION SYMPOSIUM
protein concentration is not related to plasma Ca
concentration when chickens were fed diets with
different Ca concentrations [107]. Emtage et al.
[108, 109] demonstrated that intestinal chicken
mucosa has the ability to synthesize calbindin
D28k in response to vitamin D, and that intra-
cardial administration of vitamin D increases Ca
absorption 12 h after treatment [108, 109]. It has
been shown by several authors that vita-min D is
required for calbindin D28k synthesis in chicken.
Chickens fed a low-Ca diet supple-mented with
adequate vitamin D concentrations had increased
Ca absorption and calbindin D28k expression
[110]. In contrast, chicks that were raised on a
vitamin D-deficient diet did not ex-hibit the same
adaptation pattern to changes in dietary Ca
concentration as those seen in chicks fed an
adequate vitamin D diet [110]; similar results
were observed by others [107, 111]. Re-strictions
in dietary Ca and P in the presence of adequate
vitamin D were characterized by an alteration in
intestinal calbindin D28k [111]. In general,
chickens that were vitamin D-depleted had lower
Ca plasma concentrations, calbindin D 28k mRNa,
and protein expression in the intes-tine and kidney
[111]. Bar et al. [111] suggest that changes in
intestinal calbindin D 28k and its mRNA are not
attributable to changes in plasma Ca content, and
that induction or regulation of calbindin D28k
required vitamin D metabolites. In contrast, renal
calbindin D 28k protein and mRNA expression
patterns are positively cor-related to Ca plasma
concentration [104, 111, 112]. Intestinal calbindin
D28k, which is con-sidered to be an indicator of
Ca absorption, was found to be higher in fast-
growing broilers compared with the slower-
growing chicks from a layer strain when dietary
Ca was 1% [9, 113, 114]. High dietary Ca
concentrations suppressed calbindin D28k protein,
with maximal suppres-sion in fast-growing chicks
fed diets contain-ing 1.5%, whereas, in slow-
growing layer strain chicks, maximal suppression
was seen when a 1% Ca diet was fed [9].
The extrusion or movement of Ca across the
basolateral membrane is mediated through plas-
ma membrane calcium pump (PMCA) [115]
and sodium or calcium exchanger [116, 117].
Plasma membrane calcium pump homolog has
been cloned and characterized in chickens by
Cai et al. [118]. Chicken PMCA protein shared
615
96% homology with mammalian PMCA1b
[118]. Similar to mammals, PMCA1b is the pre-
dominant isomer expressed in the chicken intes-
tine [119, 120] and kidney [121, 122]. Plasma
membrane calcium pump mRNA is present in all
3 segments of the chicken small intestine, and its
expression was elevated after vitamin D or
1,25(OH)2D3 treatment in comparison to vi-tamin
D-depleted chickens [118]. The number of
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intestinal Ca pump units [119] and mRNA
concentration of PMCA [114] were increased in
chickens adapted to diets low in Ca and P.
The sodium or calcium exchanger has been
shown to have a limited role in intestinal Ca
transport [57], even though it is expressed in
the basolateral membrane of intestinal
enterocytes [97, 123]. In contrast, the sodium
or calcium exchanger is the main component of
Ca extru-sion in the kidney [116, 117]. As in
mammals, chicken homologs of sodium or
calcium ex-changer were expressed in intestine
and have been shown to be induced in response
to Ca de-ficiencies [124].
Bones. In the skeleton, 1,25(OH)2D3 togeth-er
with PTH promotes mobilization of Ca from bone
to maintain a constant blood Ca concen-tration
[125]. Osteoclasts do not have the PTH receptor;
therefore, activation of bone resorption occurs
indirectly via osteoblasts. Parathyroid hormone
enhances expression of the receptor activator of
NF-κB ligand (RANKL) in osteo-blasts [126]. In
turn, RANKL induces forma-tion, activation, and
survival of bone-resorbing osteoclasts [127].
Expression of RANKL is regulated by
1,25(OH)2D3 and PTH through un-usual
regulatory enhancers located at a signifi-cant
distances upstream of its transcription start site
[32].
Phosphorus Homeostasis
It has been shown that P absorption across the
intestinal brush border membrane involves both
Na-dependent and Na-independent path-ways
[128–130]. The Na-dependent transport is not
affected by changes in Ca concentration, therefore
Ca and P transport seems to be operat-ing
separately [129, 131, 132]. The Na-indepen-dent
transport in the intestine seems to be unreg-ulated
[133–135]. It has been suggested that a large
phosphate concentration in digesta after a
616
meal could induce paracellular transport
(move-ment of ions along the gradient through
spaces between cells from lumen to blood) that
could become the predominant postprandial
pathway largely responsible for overall
phosphate trans-port. However, apparently, the
intestinal epithe-lial wall is not readily
permeable to phosphate [136].
Transepithelial active transport of P in renal
tubules or intestinal tissue involves uptake of P
through the apical brush border membrane by the
Na-dependent cotransporter, translocation across
the cell, and efflux at the basolateral mem-brane
[137]. Little is known about the transport across
the cell or about the mechanism involved in the
efflux of P at the basolateral membrane in both
mammals and birds [137, 138].
P Transporters. Three classes of Na-P co-
transporters have been identified in mammals. On
an mRNA level, cotransporters represent 15, 84,
and 1% of the total Na-P cotransporter mRNA
expressed for types I, II, and III, respec-tively
[139, 140]. Type I Na-P cotransporter is expressed
predominantly in brush border mem-brane of the
proximal tubules in the kidneys and liver, and
mediates the flux of chloride, organic anions, and
P from the tubular lumen across the kidney tubule
brush border membrane into the cells [141, 142].
Its expression and activity are not regulated by
dietary P or PTH, and its role in P homeostasis is
unclear [143].
The role of type III Na-P cotransporters (PiT1
and PiT2) have not been well defined in avian
species, whereas their role is better known in
mammals. Type III Na-P cotransporters are
expressed in most tissues in mammals; PiT2 is
predominantly present in the renal brush border
membrane [144, 145], whereas PiT1 is associ-
ated within intestinal brush border membrane
[146] and the abundance of these proteins is
controlled by dietary P [144–146]. The PiT1 is
also detected in parathyroid gland and is upregu-
lated by 1,25(OH)2D3 and low dietary P, factors
that also downregulate PTH secretion [147]. It has
been postulated that PiT1 in the parathyroid gland
can serve as an inorganic P sensor that controls
PTH secretion in response to plasma
1,25(OH)2D3 and dietary P concentrations [148].
It has also been suggested that PiT2 can play an
important role in the regulation of intestinal P
absorption [134]. Treatment of vitamin D-defi-
JAPR: Symposium
cient animals with 1,25(OH)2D3 led to increased
Na-P cotransport in the brush border membrane
and upregulation of PiT2 mRNA expression in the
intestinal epithelium without changes in Na-P IIb
mRNA [135]. Moreover, a switch from a high- to
low-P diet led to upregulation of the PiT2 protein
in the brush border membrane. In contrast, a
switch from low- to high-P diet de-creased the
amount of PiT2 in the brush border membrane
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[144]. The role of both cotransport-ers, PiT1 and
PiT2, has not been yet character-ized in chickens.
Genes for both PiT1 and PiT2 are located on
chromosome 2 and 4 of the chick-en genome
(ENSGALT00000022329 and EN-
SGALT00000032235, respectively). However, the
expression pattern of those 2 genes, as well as
their involvement in P homeostasis, remains to be
determined in avian species.
Type II contransporters, IIa, IIc, and IIb, are
expressed exclusively in the renal and intestinal
brash border membrane in mammals and chick-
ens, respectively [128, 149, 150]. The Na-P-IIa
transporter has been shown to be responsible for
70 to 80% of P transport in the mouse kidney
[137]; in contrast, Na-P IIc has been thought to
have only a minor role in P transport in other
mammals [151]. Diet-induced changes in plasma
P lead to quick changes in Na-P IIa transporter at
the protein level, but prolonged deficiencies in P
concentration lead also to changes of this trans-
porter at the mRNA level. The PTH and high di-
etary P inhibit Na-P cotransport across the brush
border membrane by triggering retrieval of Na-P
IIa and IIc from the brush border membrane
through endocytosis. In contrast, low dietary P
increases brush border membrane Na-P cotrans-
port through the recruitment of existing Na-P IIa
and IIc proteins to the epical membrane [152–
154]. Both transporters are regulated by PTH,
dietary P, and FGF23 [150, 155–157]. Similar to
mammals, in chickens PTH acts acutely and di-
rectly on the proximal tubules epithelium type II
contransporter and inhibits active transepithelial P
reabsorption [158]. This process is mediated
through both the PKA and PKC regulatory path-
ways. At the molecular level, the Na-P IIa has
been detected in chicken kidney [159] and Na-P
IIa mRNA concentrations were significantly
reduced when plasma P was elevated in laying
hens [160]. In contrast to mammals, the avian
kidney has the ability not only to reabsorb P, but
Proszkowiec-Weglarz and Angel: INFORMAL NUTRITION SYMPOSIUM
also for tubular P secretion [161]. Both process-
es are under the control and influence of PTH
[162, 163], which has been shown to stimulate
net P secretion [164, 165].
The Na-P IIb is a major P transporter that
accounts for over 90% of the Na-dependent
phosphate transport in mammals [166]. How-ever,
under low P conditions, when the Na-P IIb
expression is maximally induced, this trans-porter
contributes slightly less than half of the total acute
intestinal P absorption [166] and only 30% of
intestinal P absorption occurs in a regu-lated,
1,25(OH)2D3-dependent manner in mam-mals
[167]. Mammalian expression of Na-P IIb is
regulated by dietary P, 1,25(OH)2D3, estrogen,
and epidermal growth factor [135, 168, 169].
Parathyroid hormone does not directly regulate
Na-P IIb expression [170, 171], but it has an ef-
fect on intestinal P transport through its stimu-
latory effect on 1,25(OH)2D3 synthesis. When
intestinal Na-P IIb is downregulated, there is an
increase in renal Na-P IIa protein expression
[166] and, conversely, upregulation of the re-
nal transporter downregulates the intestinal one
[172]. The chicken homolog of Na-dependent P
transporter (Na-P IIb) has been recently cloned
by Yan et al. [173]. Chicken Na-P IIb shares 62
to 68% homology at the amino acid level with
its corresponding mammalian counterparts, as
well as with mammalian Na-P IIa [173]. Chick-
en P transporter mRNA was present in various
tissues, with the highest mRNA expression in
all segments of intestinal tissues. Among the 3
sections of chicken small intestine, the duode-
num had the highest concentration, whereas the
ileum had the lowest mRNA expression [173].
Similar expression patterns among segments of
chicken small intestine were observed by Olu-
kosi et al. [174]. Yan et al. [173] demonstrated
that P reduction in the diet (from 0.55–0.25%
nPP without changes in the Ca:nPP ratio) in-
creased Na-P IIb gene expression in all 3 seg-
ments of the chicken small intestine [173]. In
contrast, Olukosi et al. [174] reported that dif-
ferent dietary P concentration (0.25, 0.35, 0.45,
and 0.55% P) had no effect on Na-P IIb mRNA
expression in duodenum; whereas, only the
very deficient P diet (0.25% P) in the jejunum
increased transporter gene expression, and both
the very deficient (0.25% P) and marginally de-
617
ficient diets (0.35% P) in the ileum resulted in
increased Na-P IIb mRNA expression [174].
Dietary P deficiencies in chickens are associ-
ated with loss of appetite, rickets, and growth
failure [175]. Dietary P concentrations of 0.05 or
0.1% lead to reduced ash content in the tibiotarsal
bone, as well as a decrease in fat-free tibiotarsal
weight at 18 d of age [176]. Feeding P-deficient
diets has been shown to increase 1,25(OH) 2D3,
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CaBP, and Ca absorption in intestinal tissue as
well as decrease plasma P and bone formation
[177–182]. Nemere [183] reported that a range of
bovine PTH(1–34) concentrations (6.5–6,500 pM)
had the ability to stimulate P transport in chick-
perfused duodenal loops. They also re-ported
treatment with 1,25(OH)2D3 stimulated P
transport to a higher magnitude compared with
PTH. When both hormones were administered
together, no additive effect was observed [183]. In
vitamin D-deficient chicks, the P response to PTH
was less than that of Ca [36]. Vitamin D has been
shown to increase P permeability through the
chicken intestine in vivo [184]. In the chicken
intestine, 24,25(OH)2D3 has been shown to
inhibit the acute, nongenomic effects of the effect
of vitamin D on P transport [185], but the effect of
PTH on P absorption was unaf-fected by this
metabolite [183].
Wasserman and Taylor [186] reported several
findings based on studies on intestinal absorp-tion
of P in white leghorn chicks. (1) Vitamin D
significantly affected P transfer in all segments of
small intestine; in the duodenum, vitamin D only
affected P basolateral transport into the body
(blood); in the jejunum, both P absorption and
basolateral transport into the blood were af-
fected; whereas, in the ileum, all 3 components of
transport (absorption, accumulation in intes-tinal
mucosa, and movement across the baso-lateral
membrane) were increased with vitamin D
treatment. (2) Under similar conditions, the
duodenum had a higher ability to absorb P than
Ca (84% of P dose and 50% of Ca dose were
absorbed within 10 min). (3) Mucosal tissue had
higher P accumulation (retention) in comparison
with Ca (60 vs. 7%). (4) The duodenum was more
efficient in P absorption in comparison with
jejunum or ileum when the absorption was
calculated per centimeter of intestinal tissue. (5)
About 62 and 40% of labeled P was absorbed
618
in the ileum within the first 5 min after infusion in
vitamin D-treated and rachitic chicks in vivo,
respectively. (6) Ileal tissues were characterized
by a similar profile of P accumulation in mu-cosa
as for P absorption. (7) Release of P from
intestinal tissues into blood was much slower in
comparison with absorption and accumulation in
mucosa. (8) Calcium level in the intestinal lu-men
had no effect on P absorption. (9) Vitamin D
treatment effects were visible within hours post-
treatment (the first significant increase in P
absorption was observed after 16 h posttreat-
ment, whereas 48 h was required for P transfer
from the cells into blood) [186].
Phosphatonins. A group of factors named
phosphatonins have emerged as major regula-
tors of phosphate homeostasis in mammals and
suggest the existence of a network of humoral
interactions and feedback loops involving the
intestine, kidney, parathyroid gland, and bone
[187]. Phosphatonins, such as FGF23 and
FGF7, were shown to secreted frizzled-related
protein 4 (sFRP-4) and matrix extracellular
phospho-glycoprotein (MEPE), which have
been shown to inhibit renal phosphate
absorption in vitro and in vivo; only FGF23
and sFRP-4 are considered to play an important
role in the regulation of 1,25(OH) 2D3 synthesis
in mammals, however [188–191].
The phosphatonin FGF23 is produced pri-
marily in bone osteoblasts and osteocytes in
mammals [192, 193]. Dietary P [194] and serum
1,25(OH)2D3 stimulate FGF23 synthesis [195].
Renal responses to FGF23 involve effects on P
transport proteins and the regulation of vita-min D
activation in mammals. It has been re-ported that
single injection of FGF23 in mice led to
suppression of P, PTH, and 1,25(OH) 2D3 serum
concentration, as well as to decreased renal Na-P
IIa and 25(OH)D3 1α-hydroxylase mRNA [196,
197]. The systemic role of FGF23 in P
homesostasis in mammals has been recently
reviewed by Crenshaw et al. [198]. In contrast to
the kidney, the role of those proteins in in-testinal
phosphate absorption is limited. How-ever, it has
been shown that injection of FGF23 into normal
mice led to a reduction in plasma 1,25(OH) 2D3
followed by inhibition of intes-tinal absorption
and Na-P IIb protein expres-sion [199]. The
MEPE is also expressed in the
JAPR: Symposium
small intestine with the highest concentration in
the duodenum, suggesting that MEPE might be a
local regulator of phosphate transport in both the
kidney and small intestine [138]. A recent study
by Marks et al. [200] showed an inhibitory effect
of MEPE on intestinal absorp-tion, but this effect
was limited to the jejunum and was independent
of changes in circulating 1,25(OH) 2D3. Although,
the role of other phos-phatonins in intestinal
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phosphate transport is unclear [138], the intestine
is suggested to be an important player in acute
phosphate regula-tion through the release of
phosphatonins [201]. The role of FGF23 and other
phosphatonins in phosphate homeostasis in
chickens has not yet been investigated. However,
Bobeck et al. [202] reported that chicks with
circulating anti-FGF23 antibody fed P-deficient
diets were characterize by normal P plasma
concentration and bone ash comparable with
chicks fed an adequate-P diet. Therefore, as in
mammals, FGF23 is involved in the regulation of
phosphate excretion and neu-tralization of FGF23
reduced the P requirements of growing chicks.
Renal-Gastrointestinal Tract Axis. Recently,
the presence of the renal-gastrointestinal tract axis
with the ability to respond rapidly (within minutes
of administration of phosphate into the intestine)
to changes in intestinal phosphate concentration
has been proposed in mammals
[201]. This signal apparently originates in the
duodenum and jejunum and is independent of
serum P concentrations, PTH, FGF23, sFRP-4,
and the action of renal nerves [201]. Those au-
thors reported the infusion of sodium phosphate
into the duodenum was associated with a rapid
increase in the renal excretion of P, even in para-
thyroidectomized rats, which was independent of
changes in plasma PTH, FGF23, or sFRP-4. They
hypothesized that the long-term adaptation to
dietary P is likely to involve factors such as PTH
or phosphatonins [189, 203–205], whereas the
short-term adaptation to dietary P involves
intestinal factors that play a role in the rapid in-
crease of renal phosphate excretion but are yet
unknown [201]. Marks et al. [138] suggest that
MEPE could be the substance with phosphato-
nin-like actions in the kidney that is secreted by
small intestine mucosa that was proposed by
Berndt et al. [201].
Proszkowiec-Weglarz and Angel: INFORMAL NUTRITION SYMPOSIUM 619

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Figure 2. Proposed model depicting Ca (A) and P (B) metabolism in broiler chickens. See text for details. CaR
= calcium sensing receptor; 1,25(OH) 2D3 = active vitamin D3; FGF23 = fibroblast growth factor 23; Na-P IIa and
IIb – sodium-P cotransporters IIa and IIb; NCX1 = sodium and calcium exchanger; PMCA1b = plasma membrane
calcium pump; PiT1 and 2 = Na-P cotransporters type III; PTH = parathyroid hormone; PTH-R = PTH receptor;
TRPV5 and 6 = epithelial Ca-selective anion channels 5 and 6; VDR = vitamin D receptor. Color version available
in the online PDF.
620
Calcium and Phosphorus
Homeostasis in Chicken
Based on the high homology of PTH, VDR,
VDRE, CaR, and Ca and P transporters in the
chicken in comparison with those in the mam-
malian system and on available research data, all
elements of Ca and P homeostasis play a
conserved role in this process. In Figure 2 is the
proposed model describing the Ca and P
metabolism pathways in broiler chickens based on
current knowledge and as interpreted by the
authors. When examining Ca homeostasis, a Ca-
deficient diet or an increase in Ca requirements
results in a decrease in plasma Ca concentra-tion.
Low plasma Ca concentrations lead to an increase
in PTH release, which, in turn, leads to activation
of 1α-hydroxylase in the kidney and Ca and P
release from bones. Increased produc-tion of
1,25(OH)2D3 in the kidney results in in-creased
absorption of Ca in the small intestine and
reabsorption of Ca in kidney. In both cases,
vitamin D acts a transcription factor inducing the
expression of Ca transporters. Moreover,
1,25(OH)2D3 has an ability to bind to the VDR-
like receptor associated with plasma membranes
and affect Ca absorption in the intestine within a
very short time (minutes). Increased PTH plas-ma
concentration stimulates CaR mRNA ex-pression,
whereas elevated 1,25(OH) 2D3 plasma
concentrations have a negative effect on the PTH
mRNA concentration, thus reducing the plasma
PTH concentration through a negative feedback
mechanism. Together, these mechanisms result in
Ca plasma concentrations returning to nor-mal
(Figure 2A). Much less is known about P
homeostasis in broilers; when chicken are fed a P-
deficient diet or P requirements are elevated,
plasma P concentration falls. A low-P plasma
concentration leads to the activation of active
vitamin D synthesis in the kidney that, in turn,
leads to increased P absorption and reabsorption
in the small intestine and kidney, respectively. At
the same time, bone resorption is induced to
maintain a normal plasma P concentration. On the
molecular level, P deficiency has been as-sociated
with increased Na-P IIb and calbindin
D28k in the small intestine and an increased con-
centration of Na-P IIa in the kidney. Moreover,
based on indirect evidence, FGF23 in chicken
decreases P reabsorption in kidney. An elevated
JAPR: Symposium
concentration of PTH has been shown to de-
crease P reabsorption and increase P secretion
in chicken kidney. How P is transported within
a cell and how it is extruded from the cells re-
mains unknown in birds as well as in mammals.
CONCLUSIONS AND APPLICATIONS
1. Based on current knowledge, Ca and P
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homeostasis in birds appears to be very
similar to that in mammals.
2. Calcium and, to a lesser extent, P are
tightly regulated in plasma. This results
in changes that affect dCa and dP at the
intestinal tract level.
3. digestible P work is usually done under
deficient conditions.
4. digestible Ca and dP change when there
is a diet deficiency; therefore, dP values
determined under deficient conditions
will be influenced by homeostatic
mech-anisms and its applicability to
commer-cial diet levels is questionable.
5. Timing of homeostatic mechanisms has
to be defined in order to establish a time
frame for dP and dCa work.
6. work is needed to define the length of
time between the starting to feed a de-
ficient diet and measurable changes oc-
curring in dCa and dP.
7. The impact of digestibility changes on
dCa and dP when deficient diets are
used, as in most P and phytase studies,
needs to be defined in order to assess
the applicability of the results obtained
with current methodologies.
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