PTHrP

PTHrP, or parathyroid hormone-related peptide, is a peptide hormone encoded by the PTHLH gene in humans. It is produced by many tissues and acts primarily in a paracrine or autocrine manner rather than as a circulating endocrine regulator. The PTHLH gene generates several isoforms through alternative splicing, and the PTHrP protein is synthesized as a prepropeptide that is processed to a shorter, bioactive N-terminal peptide that binds to the PTH1 receptor (PTH1R). Binding to PTH1R activates intracellular signaling cascades, including the cAMP/PKA and phospholipase C pathways, influencing calcium and phosphate handling and cell differentiation. In addition to extracellular signaling, PTHrP may have intracellular and nuclear roles that can influence gene expression.

Physiologically, PTHrP is essential for development: it regulates endochondral bone development and chondrocyte maturation, participates in tooth eruption, and influences mammary gland development. It also mediates placental calcium transfer to the fetus and contributes to calcium homeostasis in fetal life and postnatally in various tissues, notably bone and kidney. PTHrP functions thus complement those of parathyroid hormone (PTH) but largely through local signaling rather than systemic release.

Clinical relevance includes its role in pathology when produced by tumors. Ectopic PTHrP secretion causes humoral hypercalcemia of malignancy (HHM), a common cause of hypercalcemia in cancer, especially with squamous cell carcinomas of the lung and head and neck, as well as breast and renal carcinomas. In HHM, PTHrP promotes bone resorption and renal calcium reabsorption, often with suppressed endogenous PTH. Measurements of PTHrP can assist in diagnosis and monitoring, while treatment targets hypercalcemia and the underlying tumor. Mutations or disruption of PTHLH signaling in models produce skeletal defects, underscoring PTHrP’s developmental significance.