Parathyroid hormone (PTH)-related protein (107-139) (PTHrP(107-139)) and PTHrP(107-111) have been reported to be potent inhibitors of isolated osteoclast 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(107-139) for 24 h caused a dose-dependent increase in cell number, [3H]thymidine and [3H]phenylalanine incorporation in cultured osteoblasts. The effect was apparent at concentrations of 10-10 M and greater and was sustained 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) also stimulated all three activities but was only one tenth as potent as PTHrP(107-139). PTHrP(107-139) had no effect on osteoblast apoptosis. It is concluded that PTHrP(107-139) is not only an inhibitor of osteoclastic bone resorption but that it also stimulates osteoblast growth. This activity resides 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.