section 37.1
Calcium and Phosphorus
887
Parathyroid Hormone-Related Protein
A second m em ber o f the parathyroid horm one fam ily,
parathyroid hormone-related protein
(PTHrP), is quite
sim ilar to PTH in am ino acid sequence and protein struc-
ture. Like PTH, it activates the parathyroid horm one re-
ceptor causing increased bone resorption and renal tubular
calcium reabsorption. Increased serum concentrations o f
parathyroid horm one-related protein are the predom inant
cause o f hypercalcem ia in cancer patients with solid tu-
m ors. This observation led to its discovery and to the elu-
cidation o f its m any cellular functions in normal tissues.
In contrast to PTH, w hich is expressed only in parathy-
roid glands, PTHrP is detected in m any tissues in fetuses
and adults; it is found in epithelia, m esenchym al tissues,
endocrine glands, and the central nervous system . This
protein is also the principal regulator o f placental calcium
transport to the fetus.
T he functions o f PTHrP have com e prim arily from stud-
ies in m ice in w hich the parathyroid horm one-related gene
has been deleted or altered in other w ays. L oss o f the pro-
tein is lethal in m ice; w ithout an active gene, m ice die
shortly after birth due to defects in cartilage developm ent.
T he results o f both loss o f function (h om ozygou s knockout
o f the gen es) and gain-of-function experim ents (targeted
overexpression o f the gene in cartilage) show that PTHrP
accelerates the growth o f cartilage cells and blocks their
progression to a term inally differentiated state. It plays a
key role along w ith other proteins (such as the hedgehog
protein identified in
Drosophila
) in shaping the pattern o f
the trunk and lim bs. R eceptors for PTHrP are present on
proliferating chondrocytes and help determ ine w hether the
cell (a) continues to proliferate or (b) term inally differen-
tiates and prepares to m ineralize the cartilaginous matrix.
Patients w ith
Jansen ’s disease
have a constitutively acti-
vated PTHrP receptor gene in bone and kidney and suffer
from hypercalcem ia and delayed maturation o f chondro-
cytes.
PTHrP is released during lactation and its levels in-
crease about
1 0
,
0 0 0
-fold over the levels found in the serum
o f nonlactating w om en. R eceptors for PTHrP are present
in the intestinal epithelium and the horm one m ay play a
p h ysiologic role in the developm ent o f the alim entary tract.
H ow ever, infants raised on soy m ilk form ulas that do not
contain the horm one are healthy; thus, the horm one is not
essential.
PTHrP is a polyhorm one that is cleaved into three frag-
m ents by cells that secrete it. The N -term inal fragm ent
con sists o f am ino acids 1 -3 6 and has a PT H -like activ-
ity in breast, skin, and cartilage. The m id-region fragm ent
term inates at am ino acid 94, 95, or 101, and is involved
in placental calcium transport. The C -term inal fragm ent
is called osteostatin and is involved in bone resorption.
Calcitonin.
Parafollicular cells (C cells) scattered throu-
ghout the thyroid gland synthesize, store, and secrete cal-
citonin (thyrocalcitonin). T hese cells are derived from
neural crest cells that fuse with the thyroid gland. In non-
m am m alian vertebrates, they remain together as discrete
organs, i.e., ultim obranchial bodies. C ontinuous secretion
o f calcitonin occurs in eucalcem ia, w hile hypercalcem ia
and h ypocalcem ia m odulate this secretion. Gastrin, pen-
tagastrin, cholecystokinin, and glucagon stim ulate release
o f calcitonin, but there is no evidence that they are phys-
iological regulators. The half-life o f plasm a calcitonin is
about 10 m inutes. It is increased in patients with renal fail-
ure, w hich suggests that, since little calcitonin is found in
the urine, it is probably degraded in the kidney.
T he calcitonin precursor contains about 135 am ino acid
residues (M .W . ~ 15,000) from w hich the am ino and car-
boxy term inal sequences are rem oved to yield the active
peptide o f 32-am inos-acid residues (M .W . 3590). C alci-
tonin from hum ans contains a disulfide bridge betw een
am ino acids 1 and 7 and a C-term inal proline am ide (Figure
37-5). Salm on calcitonin, the type m ost frequently used
clinically, is 2 5 -1 0 0 tim es as potent as hum an calcitonin.
Increased resistance to degradation and tighter binding
to m em brane receptors m ay contribute to the increased
potency.
T he principal target organ for calcitonin is bone, but
renal excretion o f calcium and phosphate is also directly
affected. In bone and kidney, calcitonin activates adenylate
cyclase by binding to a distinct class o f G -protein-coupled
receptors. C alcitonin m ay also exert effects on cytosolic
C a2+ and IP
3
levels by activation o f the phospholipase
FIGURE 37-5
Amino acid sequence of human calcitonin. [Reproduced with permission
from R. K. Murray, D. K. Granner, R A. Mayes, and V. W. Rodwell,
Norwalk
H a r p e r ’s B io ch em istry,
21st ed. Appleton & Lange, Norwalk,
1988. 1988 © Appleton & Lange. ]
