PARATHYROID HORMONE-RELATED PEPTIDE DELAYS TERMINAL DIFFERENTIATION OF CHONDROCYTES DURING ENDOCHONDRAL BONE-DEVELOPMENT

To test the hypothesis that PTH-related peptide (PTHrP) is a paracrine regulator of endochondral bone development, we localized PTHrP and it s cognate receptor during normal skeletal development at both messenge r RNA (mRNA) and protein levels and compared the growth plate phenotyp es of PTHrP-deficient [(PTHrP(-/-)] mice to those of normal littermate s [PTHrP(+/+)]. PTHrP mRNA was expressed adjacent to uncavitated joint s, in the perichondrium of long bones and to a lower level in prolifer ating chondrocytes. In contrast, PTHrP protein was most evident at the interface of proliferating and hypertrophic zones, where it colocaliz ed with PTH/PTHrP receptor mRNA and protein. Most strikingly, the prol iferating zone was dramatically shorter in PTHrP(-/-) cartilage, altho ugh the percentage of cells in S-phase of the cell cycle in the prolif erating zone was indistinguishable between PTHrP(+/+) and PTHrP(-/-) m ice. Terminal differentiation of chondrocytes, which was characterized by cell hypertrophy, apoptosis (DNA fragmentation and decreased bcl-2 mRNA expression), and matrix mineralization, was more advanced in gro wth cartilage of PTHrP(-/-), compared with PTHrP(+/+) animals. These d ata demonstrate that PTHrP acts principally as a paracrine factor, whi ch promotes elongation of endochondral bone by restraining or delaying the pace of chondrocytic development and terminal differentiation of growth-plate chondrocytes.