ABSTRACT: BACKGROUND: Apoptosis of osteoblasts and osteoclasts regulates bone homeostasis. Skeletal injury in humans results in 'angiogenic' responses primarily mediated by vascular endothelial growth factor(VEGF), a protein essential for bone repair in animal models. Osteoblasts release VEGF in response to a number of stimuli and express receptors for VEGF in a differentiation dependent manner. This study investigates the putative role of VEGF in regulating the lifespan of primary human osteoblasts(PHOB) in vitro. METHODS: PHOB were examined for VEGF receptors. Cultures were supplemented with VEGF(0-50 ng/mL), a neutralising antibody to VEGF, mAB VEGF(0.3 ug/mL) and Placental Growth Factor (PlGF), an Flt-1 receptor-specific VEGF ligand(0-100 ng/mL) to examine their effects on mineralised nodule assay, alkaline phosphatase assay and apoptosis.. The role of the VEGF specific antiapoptotic gene target BCl2 in apoptosis was determined. RESULTS: PHOB expressed functional VEGF receptors. VEGF 10 and 25 ng/mL increased nodule formation 2.3- and 3.16-fold and alkaline phosphatase release 2.6 and 4.1-fold respectively while 0.3 ug/mL of mAB VEGF resulted in approx 40% reductions in both. PlGF 50 ng/mL had greater effects on alkaline phosphatase release (103% increase) than on nodule formation (57% increase). 10 ng/mL of VEGF inhibited spontaneous and pathological apoptosis by 83.6% and 71% respectively, while PlGF had no significant effect. Pretreatment with mAB VEGF, in the absence of exogenous VEGF resulted in a significant increase in apoptosis (14 vs 3%). VEGF 10 ng/mL increased BCl2 expression 4 fold while mAB VEGF decreased it by over 50%. CONCLUSION: VEGF is a potent regulator of osteoblast life-span in vitro. This autocrine feedback regulates survival of these cells, mediated via a non flt-1 receptor mechanism and expression of BCl2 antiapoptotic gene.