Advanced glycation end products (AGEs) are involved in osteopenia in people with diabetes and the elderly. Interleukin-6 (IL-6) and vascular endothelial growth factor-A (VEGF-A) are potent regulators of bone metabolism, and in bone tissue, osteocytes are an important source of these regulators. However, whether AGEs can directly regulate IL-6 and VEGF-A secretion by osteocytes is unknown. In this study, we evaluated the effect of AGEs on IL-6 and VEGF- A production as well as apoptosis in osteocyte-like MLO-Y4 cells. We also studied the involvement of receptor for advanced glycation end products (RAGE) and the role of extracellular signal-regulated kinases 1 and 2 (ERK1/2), P38 and signal transducer and activator of transcription 3 (STAT3) signalling pathways. We found that 100 μg/ml AGEs significantly induced apoptosis and up-regulated the expression of IL-6 and VEGF-A in MLO-Y4 cells. Additionally, AGEs significantly activated the ERK1/2, P38 and STAT3 signalling pathways. The ERK1/2 inhibitor U0126, the P38 inhibitor SB239063 and the STAT3 inhibitor S3I-201 all attenuated the effects of AGEs on MLO-Y4 cell apoptosis and IL-6 and VEGF-A secretion. Moreover, activation of the three signalling pathways was abolished by their respective inhibitors. Additionally, the AGEs-induced effects, including increased apoptosis, up-regulated expression of IL-6 and VEGF-A and activation of the three signalling pathways, were all abolished by pre-treating the osteocytes with the RAGE antagonist FPS-ZM1. Together, these data convince us that AGEs can activate the ERK1/2, P38 and STAT3 signalling pathways via RAGE and that their activation involves the AGEs-induced up-regulation of IL-6 and VEGF-A production as well as apoptosis in osteocytes. These results highlight the role of osteocytes in the regulation of bone metabolism by AGEs.