The parathyroid hormone-related protein system: more data but more unsolved questions

The present review focuses on recent studies that might be considered as the most relevant advances in the parathyroid hormone-related protein field, with special emphasis on proven functions in renovascular and cardiovascular systems, in physiological as well as pathological conditions. Thus, the questions as to whether and how parathyroid hormone-related protein intervenes in vascular development and homeostasis and in vascular diseases such as hypertension, atherosclerosis, restenosis and heart failure have begun to be unraveled.

Since its discovery from hypercalcemia-associated tumors in 1987, it has become clear that parathyroid hormone-related protein is a ubiquitously expressed poly-hormone and plays crucial roles in normal life. The early lethality to parathyroid hormone-related protein knockout mice emphasizes the crucial roles of the protein in development but has limited the use of these models. However, data accumulated from transgenic animals overexpressing the protein in particular cells have provided considerable support to its physiological and pathological relevance. The recent demonstration that nascent parathyroid hormone-related protein not only follows the secretory pathways, but also directly translocates to the nucleus, is beginning to uncover new actions for the protein in a number of physiological systems such as bone, mammary gland and vascular smooth muscle, as well as in pathological situations, such as cancer, osteoporosis, sepsis, atherosclerosis and hypertension.

The development of mice with conditionally deleted parathyroid hormone-related protein or parathyroid hormone-1 receptor alleles will allow the creation of cell- or tissue-specific parathyroid hormone-related protein knockout mice which will greatly facilitate the determination of the biological relevance of this protein in a specific cell or tissue type, particularly in the cardiovascular system.