The Biologic Action of Parathyroid Hormone-Related Peptide on Bone and Cartilage Cells

Abstract

Parathyroid hormone–related peptide (PTHrP) was originally identified as a factor inducing malignancy-associated hypercalcemia by activating a common receptor (PTH/PTHrP receptor) with PTH. Recently, PTHrP gene "knock-out" mice showed a form of dyschondroplasia due to reduced proliferation of chondrocytes. In addition, heterogenous populations of variously differentiated chondrocytes were seen in the hypertrophic zone of the mutant epiphyseal plate. Although the homozygotes die within several hours after birth, the adult mice heterozygous for PTHRP gene deletion display a delayed skeletal abnormality that is apparent at 3 months of age, which expresses a reduced amount of PTHrP transcript. Therefore PTHrP appears to modulate cell proliferation and differentiation at both fetal and adult stages. The colocalization of PTHrP and its receptor in osteoblastic cells and chondrocytes suggested a paracrine/autocrine mode of action. More recently, region 87–107 of the amino acid sequence of PTHrP was reported to contain a putative nucleolar localization sequence. Although the presence of the leader sequence of PTHrP preferentially targets this protein to the secretory pathway, COS-7 cells and chondrocytic CFK-2 cells, which were transfected with plasmids expressing PTHrP with or without the leader sequence, both showed nucleolar localization of both forms of PTHrP. Thus PTHrP appears to regulate normal proliferation and differentiation of bone and cartilage cells by activating the PTH/PTHrP receptor, and possibly by directly acting on the nucleus of target cells.