Biological action of parathyroid hormone (PTH)-related peptide (PTHrP) mediated either by the PTH/PTHrP receptor or the nucleolar translocation in chondrocytes

Parathyroid hormone (PTH)-related peptide (PTHrP) has been believed to act by binding the common receptor to PTH (PTH/PTHrP receptor). However, PTHrP is localized not only in the secretory pathway, but also in nucleoli by virtue of its nucleolar targeting signal (NTS). This review demonstrates the bipartite action of PTHrP on chondrocytes, the receptor-mediated and -independent signaling pathway. Mice with deletion of the PTHrP gene were characterized by a chondrodysplasia due to markedly reduced proliferation of epiphyseal chondrocytes. The PTH/PTHrP receptor was localized mainly in proliferative chondrocytes in the epiphyseal cartilage, indicating that PTHrP modulates normal proliferation via the receptor. In contrast to the receptor-mediated action, the mid-region of the amino acid sequence of PTHrP contains an NTS. The PTHrP-translation was found to initiate from both methionine-coding AUG and downstream leucine-coding CUGs in its signal sequence. When translated from CUGs, PTHrP accumulated in the nucleoli, and the translation from AUG localized PTHrP in both the Golgi apparatus and nucleoli. Therefore, nucleolar PTHrP appears to be derived from the translation initiating from both AUG and CUGs. A chondrocytic cell line expressing a full-length PTHrP, but not PTHrP lacking NTS, were resistant to apoptosis caused by serum depletion, suggesting that the nucleolar PTHrP in chondrocytes serves as a survival factor against apoptosis. Thus, PTHrP regulates chondrocyte proliferation, differentiation and apoptosis by mediating its receptor or acting directly on the nucleolus.