What is parathyroid hormone‑related protein (PTH‑rP)?

What is PTH-rP (Parathyroid Hormone-Related Protein)?

PTH-rP is a regulatory protein that shares structural homology with parathyroid hormone (PTH) at its N-terminal region, allowing it to activate the same PTH1R receptor, but serves primarily as a local paracrine/autocrine regulator in normal physiology rather than a systemic hormone, while also being the major cause of humoral hypercalcemia of malignancy when produced by certain cancers. 1, 2

Molecular Structure and Properties

• PTH-rP is a 139- to 173-amino acid protein with N-terminal homology to PTH, sharing structural similarity in the first 13 amino acids that allows it to bind and activate the PTH1R receptor 3
• The protein is encoded by a complex gene with multiple exons that can produce up to 12 alternate transcripts and three different length proteins through the use of three promoters, potentially in a tissue-specific manner 1
• PTH-rP undergoes extensive post-translational processing including glycosylation and defined proteolytic cleavages, resulting in different circulating fragments with potentially distinct biological activities 3
• The primary amino acid sequences of both PTH-like and non-PTH-like regions are highly conserved across species, suggesting important evolutionary functions 3

Physiological Roles in Normal Tissues

PTH-rP functions predominantly as a locally produced regulator/cytokine rather than an endocrine hormone, with five key physiological roles 2:

• Embryogenesis and fetal development: PTH-rP plays critical roles in normal bone development and skeletal formation 1, 2
• Placental calcium transport: The protein facilitates calcium transfer across the placenta during pregnancy 1, 2
• Lactation: PTH-rP is involved in mammary gland function and milk production 1, 2
• Smooth muscle relaxation: The protein has direct effects on smooth muscle tone in various tissues 1, 2
• Epithelial cell growth and calcium transport: PTH-rP regulates epithelial cell proliferation and differentiation 1, 2

Tissue Distribution and Expression

• PTH-rP is produced by a multitude of normal cells and tissues, far more widespread than originally recognized 1, 2
• The protein is expressed in prostatic neuroendocrine cells, where it may act in an endocrine-paracrine fashion involved in prostatic growth and calcium regulation in semen 4
• PTH-rP expression is detected in 86% of normal parathyroid tissue, mainly in the cytoplasm of oxyphil cells, with age-related increases in expression 5
• Expression is regulated by hormones and growth factors, and the gene displays features common with many cytokine genes 1

Pathological Role in Malignancy

PTH-rP is the major mediator of humoral hypercalcemia of malignancy (HHM), acting through PTH receptors in bone and kidney 1:

• The protein is a common product of squamous cancers and contributes to malignancy-related hypercalcemia in 10-25% of lung cancer patients 6
• Tumors secrete PTH-rP that mimics PTH actions on bone and kidney but suppresses endogenous PTH production 6
• Recent studies indicate PTH-rP is produced by many more cancers than originally recognized, including those metastatic to bone and hematological malignancies 1
• All prostatic adenocarcinomas express PTH-rP, suggesting a role in cancer biology beyond hypercalcemia 4

Biological Activities and Mechanisms

PTH-rP has multiple activities beyond classical PTH-like effects 1:

• The N-terminal region (1-34) produces classical PTH-like actions through PTH1R activation, including increased bone resorption and renal calcium reabsorption 3
• Midregion PTH-rP augments calcium transport through mechanisms distinct from PTH 3
• C-terminal peptides potently inhibit bone resorption, opposite to N-terminal effects 3
• The protein operates through established PTH1R signaling pathways including calcium mobilization, cAMP generation, and PKC activation 7

Clinical Measurement Considerations

• Several region-specific immunoassays can measure circulating PTH-rP concentrations, particularly useful in diagnosing PTH-rP-mediated hypercalcemia 3
• Molar concentrations of different regions may differ by more than an order of magnitude, reflecting diversity in processing and metabolism 3
• Current assays are very helpful in diagnosing PTH-rP-mediated hypercalcemia but are not yet sufficiently sensitive to accurately measure normal physiological concentrations 3

Key Clinical Distinctions from PTH

PTH-rP differs fundamentally from PTH in its physiological role: while PTH functions as a systemic endocrine hormone maintaining calcium homeostasis, PTH-rP acts primarily as a local paracrine/autocrine regulator in tissue development and function 1, 2. This distinction is critical—elevated PTH-rP in cancer represents pathological overproduction of what is normally a local regulatory factor, not dysfunction of calcium homeostasis per se 1.