Parathyroid hormone-related protein (PTHrP) as a regulating factor of endochondral bone formation

Parathyroid hormone-related protein (PTHrP) was first identified as a pathogenetic factor for the hypercalcemia of malignancy. Recently PTHrP is focused as a physiological paracrine factor regulating cell proliferation and differentiation in many tissues during fetal and postnatal growth. Evidence for the skeletal origin of PTHrP comes from several sources and targeted disruption of the PTHrP gene in mice has resulted in a phenotype with accelerated endochondral bone formation, suggesting PTHrP as a factor regulating chondrocyte differentiation. Indian hedgehog, one of the conserved family of hedgehog regulating segmentation of Drosophila, is found to be an upstream factor of PTHrP in a regulating pathway of chondrocyte differentiation. Moreover, Bcl-2, a protein that controls programmed cell death in several cell types, is suggested to lie downstream of PTHrP in this pathway. A point mutation of PTH/PTHrP receptor is identified in a patient with Jansen-type metaphyseal chondrodysplasia and constitutive, ligand independent activation is indicated in this mutant receptor.