INDUCTION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR EXPRESSION BY PROSTAGLANDIN E(2) AND E(1) IN OSTEOBLASTS

PGE(1) and PGE(2) are potent stimulators of bone formation. Osteogenesis is strongly dependent on angiogenesis. Vascular endothelial growth factor (VEGF), a secreted endothelial cell-specific mitogen, has been implicated in physiological and pathological angiogenesis. The aim of this study was to examine the possible role of VEGF in PG stimulation of bone formation. We found that in rat calvaria-derived osteoblast-enriched cells and in the osteoblastic RCT-3 cell line PGE(2) and E(1) increased VEGF mRNA and protein levels. The increased expression of VEGF mRNA produced by PGE(2) was rapid (maximal at 1 h), transient (declined by 3 h), potentiated by cycloheximide, and abolished by actinomycin D. PGE(2) had no effect on VEGF mRNA stability, suggesting transcriptional regulation of VEGF expression by PGE(2). Rp-cAMP, a cAMP antagonist, suppressed VEGF mRNA induced bg PGE(2), indicating cAMP mediation. The upregulation of VEGF expression by PGE(2) in the preosteoblastic RCT-1 cells was potentiated by treatment with retinoic acid, which induces the differentiation of these cells. The upregulation of VEGF mRNA by PGE(2) was inhibited by dexamethasone treatment. In addition, Northern blot analysis showed that VEGF mRNA is expressed in adult rat tibia. In summary, we documented, for the first time, the expression of VEGF in osteoblasts and in bone tissue. Stimulation of VEGF expression by PGs and its suppression by glucocorticoids, which, respectively, stimulate and suppress bone formation, strongly implicate the involvement of VEGF in bone metabolism.