1,25-DIHYDROXYVITAMIN D-3 INDUCES THE EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN OSTEOBLASTIC CELLS

Angiogenesis is a fundamental process in skeletal development and repa ir, and previous studies indicate that vascular endothelial growth fac tor (VEGF), an endothelial cell-specific angiogenic factor, may be inv olved in bone formation and repair. Therefore, we studied the hormonal regulation of VEGF expression in SaOS-2 osteoblast-like cells, both a t the protein level, and at the transcriptional level by transient tra nsfection experiments. 1,25-Dihydroxyvitamin D-3 [1,25-(OH)(2)D-3], in creased VEGF expression by approximately 3-fold, and the increase was dose dependent, with maximum stimulation between 1.0 and 10 nM of 1,25 -(OH)(2)D-3. Up-regulation of VEGF protein was detected already after 6 h of treatment. VEGF up-regulation was also observed in ROS-17/2.8 a nd OHS-4 osteoblast-like cells but not in MCF-7 and MDA-MB231 breast c arcinoma cells. Dexamethasone (Dex) decreased VEGF expression to 40% o f the control, but when added together with 1,25-(OH)(2)D-3, had no ef fects on the up-regulation of VEGF by 1,25-(OH)(2)D-3. PTH1-34 stimula ted weakly VEGF expression, but combined with 1,25-(OH)(2)D-3, resulte d in a close to 5-fold stimulation. A 4-day pretreatment of the cells with Dex increased the vitamin D-3 receptor expression and resulted in a stronger stimulation of VEGF by 1,25-(OH)(2)D-3, alone or in combin ation with PTH1-34. The results show that the VEGF promoter is a targe t of 1,25-(OH)(2)D-3 regulation in osteoblasts, despite the lack of cl assical vitamin D-3 responsive elements. The up-regulation of VEGF in osteoblast-like cells by calciotropic hormones provides additional evi dence of the involvement of VEGF in bone metabolism.