Physiological Reviews, Vol 76, 127-173, Copyright © 1996 by American Physiological Society
Defining the roles of parathyroid hormone-related protein in normal physiology
W. M. Philbrick, J. J. Wysolmerski, S. Galbraith, E. Holt, J. J. Orloff, K. H. Yang, R. C. Vasavada, E. C. Weir, A. E. Broadus and A. F. Stewart
Division of Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA.
Parathyroid hormone-related protein (PTHrP) was discovered as a result of a
search for the circulating factor secreted by cancers which causes the
common paraneoplastic syndrome humoral hypercalcemia of malignancy. Since
the identification of the peptide in 1982 and the cloning of the cDNA in
1987, it has become clear that PTHrP is a prohormone that is
posttranslationally cleaved by prohormone convertases to yield a complex
family of peptides, each of which is believed to have its own receptor. It
is also clear that the PTHrP gene is expressed not only in cancers but also
in the vast majority of normal tissues during adult and/or fetal life. In
contrast to the situation in humoral hypercalcemia of malignancy in which
PTHrP plays the role of a classical "endocrine" hormone, under normal
circumstances PTHrP plays predominantly paracrine and/or autocrine roles.
These apparent physiological functions are also complex and appear to
include 1) regulation of smooth muscle (vascular, intestinal, uterine,
bladder) tone, 2) regulation of transepithelial (renal, placental, oviduct,
mammary gland) calcium transport, and 3) regulation of tissue and organ
development, differentiation, and proliferation. In this review, the
discovery of PTHrP, the structure of its gene and its cDNAs, and the
posttranslational processing of the initial translation products are
briefly reviewed. Attention is then focused on a detailed organ
system-oriented review of the normal physiological functions of PTHrP.
