C‐Terminal Parathyroid Hormone‐Related Protein Inhibits Proliferation and Differentiation of Human Osteoblast‐like Cells

Parathyroid hormone‐related protein (PTHrP) is synthesized by osteoblasts, although its local role in bone is not completely understood. The C‐terminal (107–111) region of PTHrP seems to be a potent inhibitor of osteoblastic bone resorption. We studied the effect of this PTHrP domain on the proliferation and synthesis of osteoblastic markers in osteoblast‐like cells from adult human bone. We found that the human (h)PTHrP(107–139) fragment, between 10 fM and 10 nM, inhibited 3 H‐thymidine incorporation into these cells. The antiproliferative effect of the latter fragment, or that of hPTHrP(107–111), was similar to that induced by [Tyr 34 ]hPTHrP(1–34) amide, bovine PTH(1–34), and hPTHrP(1–141), while hPTHrP(38–64) amide was ineffective. Human PTHrP(7–34) amide, at 10 nM, and 1 μM phorbol‐12‐myristate‐13‐acetate also significantly decreased DNA synthesis in human osteoblast‐like cells. Neither hPTHrP(7–34) amide nor hPTHrP(107–139), at 10 nM, stimulated protein kinase A (PKA) activity in these cells. Moreover, 100 nM H‐89, a PKA inhibitor, did not eliminate the inhibitory effect of hPTHrP(107–139) on these cells' growth. However 100 nM calphostin C, a PKC inhibitor, blunted this effect of PTHrP(107–139). In addition to their antimitogenic effect, hPTHrP(107–139) and hPTHrP(107–111) inhibited basal and 1,25‐dihydroxyvitamin D 3 (1,25(OH) 2 D 3 )–stimulated alkaline phosphatase activity in these cells. Both fragments, like 1,25(OH) 2 D 3 , decreased C‐terminal type I procollagen secretion into the cell‐conditioned medium, but osteocalcin secretion by these cells was unaffected by the C‐terminal PTHrP fragments. These findings suggest that PTHrP may act as a local regulator of bone formation.