Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein

Parathyroid hormone (PTH)-related protein (107-139) (PTHrP(107-139)) and PT HrP(107-111) have been reported to be potent inhibitors of isolated osteocl ast activity, and inhibition of bone resorption by PTHrP(107-139) occurs in vivo. However, the actions of C-terminal PTHrP on osteoblast activity has not been studied much. The present study addresses this issue by examining the effect of PTHrP(107-139), PTHrP(107-119), PTHrP(120-139), and PTHrP(107 -111) on the proliferation of fetal rat osteoblasts. Treatment with PTHrP(1 07-139) for 24 h caused a dose-dependent increase in cell number, [H-3]thym idine and [H-3]phenylalanine incorporation in cultured osteoblasts. The eff ect was apparent at concentrations of 10(-10) M and greater and was sustain ed over time. PTHrP(107-119) and PTHrP(107-111) had effects on cell number, DNA, and protein synthesis which were comparable to those of PTHrP(107-139 ), whereas PTHrP(120-139) was without effect, Retroverted PTHrP(107-111) al so stimulated all three activities but was only one tenth as potent as PTHr P(107-139). PTHrP(107-139) had no effect on osteoblast apoptosis. It is con cluded that PTHrP(107-139) is not only an inhibitor of osteoclastic bone re sorption but that it also stimulates osteoblast growth. This activity resid es within the pentapeptide fragment PTHrP(107-111). These findings support a possible role for C-terminal fragments of PTHrP in the normal regulation of bone cell function and, possibly, bone mass.