Page 137 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

Disorders of Calcium: Hypercalcemia and Hypocalcemia 127

through the action of an osteocyte-osteoblast “pump” in PARATHYROID HORMONE-
order to make fine adjustments in the blood calcium con- RELATED PROTEIN:
centration. 433 The later effects of PTH on bone are poten-
tially of greater magnitude and are not dependent on the A POLYHORMONE
continuous presence of hormone. Osteoclasts are primar-
PTHrP is not strictly a calcium-regulating hormone, but
ilyresponsiblefor the long-termactionofPTHonincreas- it was identified in 1982 as an important PTH-like factor
ing bone resorption and overall bone remodeling. 102,393
that plays a central role in the pathogenesis of humoral
PTH also has the potential to serve as an anabolic 480
hypercalcemia of malignancy (HHM). PTHrP is pro-
agent in bone and stimulate osteoblastic bone forma- duced widely in the body and has numerous actions in the
tion. 201,552 Intermittent administration of exogenous
developing fetus and adult animal independent of its role
1-34 PTH has been reported to increase bone mass in in cancer-associated hypercalcemia. 451 This is in contrast
humans and animals. 554 to PTH, which is produced by the parathyroid glands and
The ability of PTH to enhance the renal reabsorption functions principally in regulation of calcium balance.
of calcium is of considerable importance. This effect of PTHrP has multiple actions that are specific to the N-ter-
PTH on tubular reabsorption of calcium is caused by, minal, midregion, and C-terminal regions of the protein,
in part, a direct action on the distal convoluted tubule. 631
making PTHrP a true polyhormone.
PTH may also increase calcium reabsorption in the
Some of the actions of PTHrP involve normal regula-
ascending thick limb of Henle’s loop indirectly by 491
tion of calcium metabolism. For example, PTHrP
increasing the net positive charge in the nephron lumen
functions as a calcium-regulating hormone in the fetus
and creating a stimulus for diffusion out of the lumen. 343
and is produced by the fetal placenta. In the adult,
PTH also regulates the conversion of 25-hydroxychole- PTHrP circulates in the blood in low concentrations
calciferol to calcitriol and other metabolites of vitamin D.
(<1 pM) but is produced by many different tissues and
Parathyroid Hormone C-Terminal 7-84 as functions principally as an autocrine, paracrine, or
PTH Antagonist intracrine cellular regulator. PTHrP is produced by the
lactating mammary gland and is secreted into milk. Mam-
It was originally thought that PTH 35-84 and other
mary gland production of PTHrP likely facilitates mobi-
fragments cleaved between residues 24 and 43 dominated
lization of calcium from maternal bones and may play a
the carboxyl-terminal fragments of PTH secreted by chief
role in the transport of calcium into milk during lacta-
cells. The C-terminal fragments can be measured using 628,629
tion. PTHrP acts as an abnormal systemic cal-
C-terminal-specific immunoassays. The function of
cium-regulating hormone and mimics the actions of
PTH 35-84 and its receptor is unknown, but it may reg-
PTH in patients with HHM. PTHrP not only plays a
ulate bone cell function. The larger C-terminal fragment, major role in most forms of HHM but also has been
PTH 7-84, 279 may be significantly increased in renal sec- demonstrated in many normal tissues, including epithe-
ondary hyperparathyroidism 386 and can antagonize the lial cells of the skin and other organs; endocrine glands;
effects of PTH 1-84 in vivo. 321 The antagonistic action smooth, skeletal, and cardiac muscle; lactating mammary
of PTH 7-84 is likely attributable to binding to an alter- glands; placenta; fetal parathyroid glands; bone; brain;
nate PTH receptor and not to the PTH1 receptor that is and lymphocytes. 451,478 Therefore, PTHrP functions as
used by PTH 1-34 and PTH 1-84. 148,414
(1) a hormone in an endocrine manner in the fetus and
Parathyroid Hormone Receptor lactating dams, 582 (2) a paracrine factor in many fetal
and adult tissues, and (3) an abnormal hormone in an
The receptor for N-terminal PTH (amino acids 1 to 34),
endocrine manner in adults with HHM (Fig. 6-8).
the region important in calcium regulation, has been
PTHrP is necessary for normal endochondral bone for-
cloned and sequenced in humans, dogs, and other spe-
1,416,542 mation in the fetus and neonate. Knockout of the PTHrP
cies. It is a seven-transmembrane domain recep- gene results in short-limb dwarfism and death at birth as a
tor that is expressed in renal epithelial cells, osteoblasts, result of a failure of cartilage proliferation at the growth
and some other cells. The N-terminal regions of PTH plates and premature ossification. 287
and PTHrP bind this receptor with equal affinity. The
PTHrP is a 139- to 173-amino acid peptide originally
PTH receptor is also located on many cell types, such
isolated from human and animal tumors associated with
as dermal fibroblasts, that are not associated with the 480
HHM. PTHrP shares 70% sequence homology with
action of PTH. It is assumed that the receptor functions
PTH in its first 13 amino acids. The N-terminal region
as the binding protein for PTHrP in these tissues. The
of PTHrP (amino acids 1 to 34) binds and stimulates
currently used terminology for this receptor is the
PTH receptors in bone and kidney cells with affinity equal
PTH1 receptor, but it is often described as the PTH/
to that of PTH, so that PTHrP functions similarly to
PTHrP receptor. The PTH2 receptor is present in the 124,423
PTH in patients with HHM. The midregion of
brain and binds to both PTH and tuberoinfundibular PTHrP is responsible for stimulating iCa uptake by the
peptide but not to PTHrP. 249