Parathyroid hormone (PTH), PTH-related peptide (PTHrP), PTHR, and their cognate G protein-coupled receptor play defining roles in the regulation of extracellular calcium and phosphate metabolism and in controlling skeletal growth and repair. Acting through complex signaling mechanisms that in many instances proceed in a tissue-specific manner, precise control of these processes is achieved. A variety of direct and indirect disease processes, along with genetic anomalies, can cause these schemes to become dysfunctional. Here, we review the basic components of this regulatory network and present both the well-established elements and emerging findings and concepts with the overall objective to provide a framework for understanding the elementary aspects of how PTH and PTHrP behave and as a call to encourage further investigation that will yield more comprehensive understanding of the physiological and pathological steps at play, with a goal toward novel therapeutic interventions.
