Intrauterine occupancy controls expression of the parathyroid hormone-related peptide gene in preterm rat myometrium.

Abstract

The parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHRP) genes are members of a gene family. Whereas PTH is a classical peptide hormone, mounting evidence suggests that the PTHRP may have predominately local actions. We report here that the PTHRP gene is expressed in rat myometrium, with a major peak in PTHRP mRNA expression occurring in the 48 hr immediately preceding parturition. A similar peak in peptide content was found in tissue extracts by biological and immunological assays, but the PTHRP could not be detected in the peripheral circulation or in uterine vein plasma during late gestation. By in situ hybridization histochemistry, PTHRP mRNA was demonstrated in both the longitudinal and circular layers of smooth muscle but was absent in the endometrium. The rise in myometrial PTHRP mRNA in late gestation was dependent upon intrauterine occupancy; it was greatly reduced or absent in nongravid uterine horns. These findings indicate that the expression of the PTHRP gene in preterm myometrium is under the control of a local stimulus and suggest that the PTIHRP may play a paracrine or autocrine role in the uterus during the antepartum period, possibly involving myometrial contractility.The parathyroid hormone-related peptide (PTHRP) was initially isolated (1-4) and its cDNA cloned (5-8) from human and animal tumors associated with the syndrome of humoral hypercalcemia of malignancy. The PTHRP has sequence similarity to parathyroid hormone (PTH) at its N terminus, which appears to account for its PTH-like actions when it is secreted into the systemic circulation by malignant tumors (9). However, the deduced PTHRP product is larger than PTH and has a more complex structure, suggesting that it may be subject to one or several posttranslational processing steps (5-8). The precise secretory form of the PTHRP has not been established for any cell type.Chromosomal localization studies and the structures of the PTH and PTHRP genes indicate that they arose by duplication from a common ancestral chromosome (10-12). Following this duplication event, the two genes have clearly evolved separately. The human PTHRP gene has been found to have an organization that is considerably more complex than that of the PTH gene (10)(11)(12)(13)(14). In addition, whereas the PTH gene is expressed predominately if not exclusively in parathyroid cells (15), the PTHRP gene is widely expressed in both endocrine and nonendocrine tissues. These sites of expression include tissues as diverse as skin (6,16,17), lactating mammary tissue (8), the chicken oviduct shell gland (18), the endocrine pancreas (19), and regions of the central nervous system (20). The role(s) of the PTHRP in these various sites is unknown, but the available evidence suggests that the peptide may be acting locally. Unique PTHRP receptors have not yet been identified.We report here that the PTHRP gene is expressed in rat myometrium and that this expression peaks in the antepartum period. This peak in PTHRP gene expression is confined to gravid ute...

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

“…Approximately 80% of hypercalcaemic patients with solid tumours have detectable or increased plasma concentrations of PTHrP (Burtis et al 1990). In addition to the diverse normal physiological functions of PTHrP, it has a multifunctional role in cancer as well.…”

“…The widespread expression of PTHrP in normal tissue was the first evidence that the hormone had a role in normal physiology. In addition to the PTH-like effects, emerging work testifies to the fact that PTHrP plays a role in (1) the regulation of cartilage differentiation and bone formation (Minina et al 2001), (2) the growth and differentiation of skin (Wysolmerski et al 1994b), mammary gland (Wysolmerski et al 1998) and teeth (Philbrick et al 1998), (3) cardiovascular function (Schluter & Piper 1998), (4) transepithelial calcium transport in mammary epithelia and placenta (Wysolmerski et al 1994a, Kovacs et al 1996, (5) relaxation of smooth muscle in uterus, bladder, arteries and ileum (Thiede et al 1990, Yamamoto et al 1992, Botella et al 1994, Pirola et al 1994) and (6) host immune function (Funk et al 1994(Funk et al , 1995. Normal subjects do not have detectable circulating levels of PTHrP, suggesting that in normal physiology PTHrP acts as a local regulator or cytokine in the tissues where it is produced.…”

“…Over the subsequent five decades investigators determined that PTH was not, in fact, the cause of humoral hypercalcaemia of malignancy (HHM), but that a 'PTH-like factor' was responsible for most cases. In 1987, this PTHrP was purified from human lung cancer , breast cancer (Burtis et al 1990) and renal cell carcinoma (Strewler et al 1987) simultaneously by several independent groups and cloned shortly thereafter . PTHrP shares 70% sequence homology with PTH over the first 13 amino acids at the N-terminus.…”

The Effect of Cytokines on Parathyroid Hormone-Related Protein (PTH-rP) Production in Human Amnion Cells.

“…While PTH gene has a simple structure and appears to be expressed principally by the parathyroid gland, the PTH-rP gene has a complex organization and is expressed in a wide variety of normal tissues and cell types including the tissues of fetus and those of the reproductive tract [2][3][4][5][6][7][8].…”

Immunolocalization of PTHrP in the parotid glands of three rodents species: Clethrionomys glareoulus, Microtus arvalis and white Swiss mice.

“…The PTHrP mRNA is responsible for the formation of three peptide isoforms with various chain length: 139, 141 and 173 amino acids [4][5][6][7]. Human tissues and neoplastic tumors may contain three transcripts, but some tissues show preference for one of the isoforms [4,5,8].…”