Parathyroid hormone-related protein is a developmental regulatory molecule

Parathyroid hormone-related peptide (PTHrP) was discovered as the tumor product that is responsible for most instances of the syndrome of humoral hypercalcemia of malignancy. It is now known that the PTHrP and PTH genes arose on the basis of an ancient duplication event. One result of this heritage is a short stretch of highly homologous sequence at the N-terminus of each of the peptides, and another is the fact that these N-terminal products seem to be serviced by a single G protein-coupled receptor referred to as the type I receptor. Overexpression and null strategies in mice have recently provided convincing evidence that one such PTHrP function is as a developmental regulatory molecule. For example, overexpression of PTHrP in keratinocytes, mammary epithelial cells and chondrocytes results in a developmental phenotype in each case, while knockout of the gene is associated with a chondrodystrophy that is lethal at birth. Rescue of the PTHrP-null mouse via a genetic strategy involving a cross between the knockout mouse and a transgenic mouse with targeted PTHrP overexpression in chondrocytes provides a window on previously unappreciated PTHrP developmental regulatory effects in multiple tissues that share a common epithelial-mesenchymal morphogenetic background.