Parathyroid Hormone-Related Protein

Parathyroid hormone-related protein (PTHrP) is actually a family of protein hormones produced by most if not all tissues in the body. A segment of PHRH is closely related to parathyroid hormone, and hence its name, but PHRH peptides have a much broader spectrum of effects. Parathyroid hormone and some of the PTHrP peptides bind to the same receptor, but PTHrP peptides also bind to several other receptors.

PHRH was discovered as a protein secreted by certain tumors that caused hypercalcemia (elevated blood calcium levels) in affected patients. It was soon shown that the uncontrolled secretion of PHRH by many tumor cells induces hypercalcemia by stimulating resorption of calcium from bone and suppressing calcium loss in urine, similar to what is seen with hyperparathyroidism. However, it quickly become apparent that PHRH had many activities not seen with parathyroid hormone.

Hormone Structures, Receptors and Sources

PTHrP is encoded by a single gene that is highly conserved among species. It should probably be described as a polyhormone, because a family of peptide hormones are generated by alternative splicing of the primary transcript and through use of alternative post-translational cleavage sites. To make matters even more complex, some cells appear to use alternative translational initiation codons to produce forms of the protein that are targeted either for secretion or nuclear localization. The figure below shows one of the characterized processing patterns of the PTHrP preprohormone, in this case yielding 3 bioactive peptides.

The diverse activities of PTHrP result not only from processing of the precursor into multiple hormones, but from use of multiple receptors. It is clear that amino-terminal peptides of PTHrP share a receptor with parathyroid hormone, but they also bind to a type of receptor in some tissues that does not bind parathyroid hormone. Moreover, it is almost certain that the midregion and osteostatin peptides bind other, unique receptors.

In addition to the secreted forms of this hormone, there is considerable evidence that a form of PTHrP is generated in some cells that is not secreted and, via nuclear targeting sequences, is translocated to the nucleus, where it affects nuclear function. The consequences of this "intracrine" mode of action are not yet well characterized, but may modulate such important activities as programmed cell death.

PTHrP is secreted from a large and diverse set of cells, and during both fetal and postnatal life. Among tissues known to secrete this hormone are several types of epithelium, mesenchyme, vascular smooth muscle and central nervous system. Although PTHrP is found in serum, a majority of its activity appears to reflect paracrine signaling.

Physiologic Effects of Parathyroid Hormone-Related Protein

One thing to recognize about PTHrP is that its name is inadequate to describe its activities. Like parathyroid hormone, some of the effects of PTHrP result from its effects on transepithelial fluxes of calcium, but many of its actions have nothing to do with calcium homeostasis. Most prominently, PTHrP peptides exert significant control over the proliferation, differentiation and death of many cell types. They also play a major role in development of several tissues and organs.

Much of our understanding of the biologic effects of PTHrP comes from experiments with genetically-altered mice. Mice with targeted deletions in the PTHrP gene (knockout mice), mice that overexpress PTHrP in specific tissues (transgenic mice), and crosses between knockout and transgenic mice have been critical in delineating many effects of this hormone. Humans with mutations in the PTHrP gene or the parathyroid receptor have also played a role in confirming the activity of PTHrP. Some of the physiologic effects of PTHrP garnered from these studies are described here:

• Cartilage and Bone Development: Mice with homozygous inactivation of the PTHrP gene die at birth, if not earlier. They manifest severe chondrodysplasia and premature epiphyseal closure, reflecting a developmental defect in proliferation and differentiation of cartilage. These and other types of studies indicate that PTHrP stimulates the proliferation of chondrocytes and suppresses their terminal differentiation. These effects of PTHrP appear due to interaction of the PTH-like peptide with the parathyroid hormone receptor.
• The mammary glands of female mice with homozygous inactivation of the PTHrP gene fail to develop, except for the earliest stages. Development of the mammary gland depends upon a complex interaction between epithelial and mesenchymal cells that apparently requires PTHrP. In normal animals, mammary epithelial cells secrete large amounts of PTHrP, which suggests a role of this hormone in adapting maternal metabolism to the calcium demands of lactation.
• Placental Transfer of Calcium: The "midregion" peptide of PTHrP (see above) has been shown to control the normal maternal-to-fetal pumping of calcium across the placenta. In the absence of fetal PTHrP, this gradient is not established.
• Smooth Muscle Functioning: PTHrP is secreted from smooth muscle in many organs, usually in response to stretching. It acts to relax smooth muscle, thereby serving, among other things, as a vasodilating hormone. Transgenic mice that express PTHrP in vascular smooth muscle manifest hypotension. PTHrP may also have effects on contraction of muscle in the bladder, uterus and heart.
• Other Effects: PTHrP is highly expressed in skin. Transgenic mice that overexpress PTHrP in skin show alopecia, and treatment of mice with a PTHrP antagonist leads to increased numbers of hair follicles and a shaggy appearance. Another interesting defect in PTHrP-knockout mice is that, although their teeth develop normally, they fail to erupt. Finally, both PTHrP and its receptors are widely expressed in the central nervous system, and appear to influence neuronal survival by several mechanisms.

It should be clear from the above examples that PTHrP hormones have profound effects on a large number of physiologic processes. Ongoing research on this polyhormone is certain to reveal additional effects in this already complex system.

References and Reviews

• Strewler GJ: The physiology of parathyroid hormone-related protein. New Eng J Med 342:177-185, 2000.
• Wysolmerski JJ, Stewart AF: The physiology of parathyroid hormone-related protein: An emerging role as a developmental factor. Annu Rev Physiol 40:431-460, 1998.

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