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. Osteogenes is 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-en riched cells and in the osteoblastic RCT-3 cell line PGE(2) and E(1) i ncreased VEGF mRNA and protein levels. The increased expression of VEG F mRNA produced by PGE(2) was rapid (maximal at 1 h), transient (decli ned by 3 h), potentiated by cycloheximide, and abolished by actinomyci n D. PGE(2) had no effect on VEGF mRNA stability, suggesting transcrip tional regulation of VEGF expression by PGE(2). Rp-cAMP, a cAMP antago nist, suppressed VEGF mRNA induced bg PGE(2), indicating cAMP mediatio n. The upregulation of VEGF expression by PGE(2) in the preosteoblasti c RCT-1 cells was potentiated by treatment with retinoic acid, which i nduces the differentiation of these cells. The upregulation of VEGF mR NA by PGE(2) was inhibited by dexamethasone treatment. In addition, No rthern blot analysis showed that VEGF mRNA is expressed in adult rat t ibia. In summary, we documented, for the first time, the expression of VEGF in osteoblasts and in bone tissue. Stimulation of VEGF expressio n by PGs and its suppression by glucocorticoids, which, respectively, stimulate and suppress bone formation, strongly implicate the involvem ent of VEGF in bone metabolism.