It have been reported that abnormal bone metabolism often occurs in patients with type 2 diabetes, but the underlying mechanisms remain to be elucidated. In recent years dyslipidemia (hyperlipidemia) has been presumed to have an influence on bone metabolism. In addition, the involvements of VEGF and MCP-1 derived from osteoblasts in bone abnormal metabolism were also observed. Thus, we investigated the pathogenic mechanism of this abnormal bone metabolism, which is included in the regulation of VEGF and MCP-1 secretions from osteoblasts, by using UMR-106 osteosarcoma cells as an osteoblast cell model and treating them with palmitate in order to mimic a state of hyperlipidemia. Palmitate-preloaded cells showed the significant increase of VEGF(120) release (1.8-fold vs. control cells, p < 0.01). Moreover, the treatment with palmitate significantly increased VEGF-A mRNA with the maximal 2.5-fold upregulation at 12 h after the treatment (p < 0.01). However, MCP-1 release was not affected by palmitate. Moreover, the amplified VEGF(120) secretion with palmitate was significantly decreased by the treatment with TLR4 antagonist or PI3K pathway inhibitors, LY294002 and wortmannin (p < 0.01, respectively). On the other hand, the stimulation with TNF-alpha, which osteoclasts were able to release, significantly enhanced MCP-1 secretion (p < 0.01), but had no effect on VEGF(120). On the contrary IL-1 beta amplified VEGF(120) release (p < 0.01), but not MCP-1. These results suggest that palmitate can increase VEGF(120) release from UMR-106 osteosarcoma cells, which is accelerated at the transcriptional level, and this increase of VEGF(120) release may be mediated though, at least partly, TLR4 and the PI3K pathways. In addition, we also verified that TNF-alpha and IL-1 beta, which are considered to be derived from osteoclasts, amplified the secretions of MCP-1 and VEGF(120) from UMR-106 cells, respectively. Crown Copyright (C) 2014 Published by Elsevier Inc. All rights reserved.