PTHrP: Novel roles in skeletal biology

Parathyroid hormone-related peptide (PTHrP) was discovered as the main medi ator of humoral hypercalcemia associated with malignancy but is now known t o be expressed by a variety of normal fetal and adult tissues. The amino-te rminal region of PTHrP reveals Limited but significant homology with parath yroid hormone (PTH), resulting in the interaction of either peptide with a common seven-transmembrane spanning G-protein linked receptor termed the PT H/PTHrP receptor. Targeted inactivation of PTHrP and its receptor in mice h as established a critical role for this signaling pathway in chondrocyte bi ology and endochondral bone formation. Animals homozygous for the targeted alleles demonstrate marked skeletal deformities arising from impaired chond rocyte proliferation, premature differentiation and accelerated apoptosis. The complex processes resulting in normal endochondral bone development inv olve additional factors such as the hedgehog signaling pathway with which P THrP interacts. PTHrP, like PTH, also binds to receptors on cells of the os teoblast lineage resulting in enhanced bone formation and also, indirectly, augmented osteoclastic bone resorption. The marked premature osteoporosis observed in mice heterozygous for the disrupted Pthrp allele also points to a crucial role for the protein in the maintenance of the adult skeleton. F urther studies into this process are likely to reveal new facets of the pat hogenesis underlying a variety of metabolic bone diseases and potentially p oint to new directions for therapeutic interventions.