section 37.1
Calcium and Phosphorus
883
tubule cells [recall that synthesis o f l,25-(O H )2D occurs
in the proxim al tubular cells], and reabsorption o f cal-
cium and phosphate is increased. In each case, the changes
brought about by 1,25-(O H )2D act on the kidney to reduce
production o f 1,25-(O H )2D , thereby form ing a regulatory
feedback loop.
U pon entry into target cells, l,25-(O H )2D m igrates into
nuclei, w here it binds w ith high affinity to the vitam in D
receptor (V D R ), w hich is a m em ber o f the nuclear recep-
tor fam ily. The binding o f l,25-(O H )2D , w hich functions
as a ligand to the nuclear receptor V D R , is analogous to
the initiation o f biochem ical action by steroid-thyroid hor-
m ones (Chapters 30 and 33). The binding o f the ligand
to V D R brings about conform ational changes so that the
retinoid X receptor (R X R ) can com bine w ith it, form ing
a heterodim er com plex. The ligand-V D R -R X R com plex
recruits additional coactivators and binds to vitam in D
response elem ents (V D R E s) in the prom oter regions o f
target genes. T he specific binding occurs via the tw o zinc
finger m odules o f the D N A binding dom ain o f the recep-
tors. The com p lex interacts w ith the general transcription
apparatus o f 1,25-(O H )2D -responsive genes. The target
genes can b e either upregulated or downregulated. A n ex -
am ple o f upregulation is calcium -binding proteins (C aB P),
w hich facilitate intestinal calcium absorption. Inhibition
o f PTH gen e expression in the parathyroid glands is an
exam ple o f downregulation.
The vitam in D receptor is w idely distributed not only
in the target tissues but also in m any other tissues such
as thyroid, skin, adrenal, liver, breast, pancreas, m uscle,
prostate, lym phocytes, and in num erous m alignant cells.
Thus, the actions o f vitam in D include regulation, prolif-
eration, differentiation, and im m unom odulation.
The im portance o f V D R in bone m etabolism arises from
studies o f polym orphism s o f the V D R gene. T hese show
that normal allelic variations in the V D R gen e m ay account
for inherited variability in bone m ass and density. Specific
alleles o f the V D R gene predict the density o f fem oral and
vertebral bone in prepubertal A m erican girls o f M exican
descent. In the developm ent o f osteoporosis, a disorder
determ ined by m ultiple genetic and environm ental factors,
variants o f the V D R gene and its products m ay play a
significant role. O ne o f the important functions o f the V D R
protein is calcium absorption.
A n autosom al recessive disease know n as
hereditary
vitamin D-resistant rickets, type II
is caused by defects
in the gen e for the vitam in D receptor w hich renders it
nonfunctional. Thus, this knockout o f V D R function il-
lustrates its im portance. Patients with this d isease have
high circulating levels o f 1,25-(O H )2D (unlike type I d is-
ease w hich is due to la-h y d ro x y la se deficiency, discussed
earlier), severe rickets, and alopecia. T he alopecia m ay
be due to d efective V D R in the hair follicles. Type II pa-
tients do not benefit from l,2 5 -(O H )2D therapy, and m ay
require both intravenous calcium therapy and high-dose
oral calcium adm inistration.
In bone, a C aB P called osteocalcin contains 4 9 am ino
acids (M .W .
5 5 0 0 -6 0 0 0 ). Its synthesis is
stim ulated
by l,25-(O H )2D . O steocalcin contains four residues o f
y-carboxyglutam ic acid, w hich require vitam in K for their
synthesis and are important as binding sites for calcium
(Chapter 36). A lthough vitam in K deficiency reduces the
osteocalcin content o f bone, it does not cause functional
bone defects. For this reason, osteocalcin m ay function in
calcium m obilization rather than deposition. A lternatively,
as an effective inhibitor o f hydroxyapatite form ation, it
m ay prevent overm ineralization o f bone. l,25-(O H )2D in-
creases
y
-glutam yl carboxylase activity in the renal cor-
tex. The relationship betw een vitam in D and vitam in K
needs clarification.
A lthough only C aBP m R N A is know n to increase in re-
sponse to vitam in D , other vitam in D -dependent changes
occur in the intestinal epithelium , including increases in
activity o f alkaline phosphatase, calcium ATPase, adeny-
late cyclase, and R N A polym erase. In response to vita-
m in D , several brush-border m em brane proteins increase
in concentration as does a calcium -binding com plex.
N on-cA M P-dependent phosphorylation o f a brush-border
m em brane protein, increased synthesis and turnover o f
m icrovillar m em brane phospholipids, and effects on m i-
tochondria, G olgi m em branes, and intracellular m em -
brane v esicles are observed. Increased transport o f Ca2+
across the basolateral m em brane m ay be produced by
1.25- (O H )
2
D.
l,2 5 -(O H )2D increases reabsorption o f phosphate in
the kidney and intestinal absorption o f phosphate. In the
intestine, phosphate is absorbed as a counterion with
Ca2+ and also by a calcium -independent route. Phosphate
flux through both pathways is increased by l,25-(O H )2D
but m ore slow ly than calcium transport. T he calcium -
independent pathway m ay involve alkaline phosphatase,
the activity o f w hich is increased by l,25-(O H )2D . In rat
intestine
in vitro,
phosphate transport is greatest in the
jejunum and least in the ileum , w hereas calcium uptake
is highest in the duodenum .
T he major excretory route for vitam in D is bile. V itam in
D m etabolites m ay undergo conjugation in the liver prior
to secretion. A n enterohepatic circulation o f 25-(O H )D ,
1.25-
(O H )
2
D , and other vitam in D m etabolites has been
dem onstrated in hum ans.
In liver disease, decrease in hepatic 25-hydroxylase
activity has little effect on serum l,25-(O H )2D con cen -
tration. E ven w hen serum 25-(O H )D concentration is
reduced in primary biliary cirrhosis, the 1,25-(O H )2D level
