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

1997; Oxford University Press; Volume: 12; Issue: 5 Linguagem: Inglês

10.1359/jbmr.1997.12.5.778

1523-4681

María E. Martinez, Adolfo Garcı́a-Ocaña, Maravillas Sánchez, Sónia Medina, M. T. del Campo, Álvaro Valín, M.J. Sanchez-Cabezudo, Pedro Esbrit,

Metabolism, Diabetes, and Cancer

Abstract 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, inhibited3H-thymidine incorporation into these cells. The antiproliferative effect of the latter fragment, or that of hPTHrP(107–111), was similar to that induced by [Tyr34]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 D3 (1,25(OH)2D3)–stimulated alkaline phosphatase activity in these cells. Both fragments, like 1,25(OH)2D3, 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.