Parathyroid hormone-(1-34) enhances aggrecan synthesis via an insulin-likegrowth factor-I pathway

During endochondral bone formation, the growth plate chondrocytes prolifera te, become hypertrophic, lose the cartilage phenotype, undergo mineralizati on, and provide a scaffold upon which subsequent longitudinal bone growth o ccurs. Parathyroid hormone (PTH), a calcium-regulating hormone, and parathy roid hormone-related peptide (PTHrP), which shares several properties with PTH, have profound effects on skeletal growth and new bone formation. In or der to define further the mechanism by which PTH/PTHrP promotes the cartila ge phenotype, chondrocytes isolated from the rib cages of developing rat em bryos were evaluated for the biosynthesis of aggrecan. Cells treated with P TH-(1-34) for a 4-h period followed by a 20-h recovery period showed a sign ificant increase in cartilage proteoglycan (aggrecan) synthesis in a dose-d ependent manner. Only N-terminally intact PTH and PTHrP were effective in s timulating aggrecan synthesis. Addition of a neutralizing antibody to insul in-like growth factor-I (IGF-I) during PTH treatment resulted in the inhibi tion of PTH-stimulated aggrecan synthesis, whereas the addition of a neutra lizing antibody to insulin-like growth factor-binding protein-2 (IGFBP-2) r esulted in an increase in synthesis in both the control and PTH-treated cel ls. In addition, PTH treatment resulted in an increase in the mRNA for aggr ecan, a reduction in IGFBP-3 mRNA, and no discernible changes in IGF-I mRNA levels, which was complemented by quantitative changes in IGFBP-3 and free IGF-I levels. The reciprocal relationship in the expression of aggrecan an d IGFBP was further confirmed in chondrocytes from various gestational stag es during normal development, Collectively, our results indicate that the e ffect of PTH may be mediated at least in part through the regulation of the IGF/IGFBP axis, by a decrease in the level of IGFBP-3, and an increase in free IGF-I levels. It is likely that the local increase in IGF-I may lead t o an increase in cartilage type proteoglycan synthesis and maintenance of t he cartilage phenotype. The consequence of the prolonged maintenance may be to halt mineralization while a new scaffolding is created.