Advanced glycation end‐products induced VEGF production and inflammatory responses in human synoviocytes via RAGE‐NF‐κB pathway activation

Aging and diabetes are known to be the major cause to affect the progression of osteoarthritis (OA). Advanced glycation end products (AGEs) have been observed to accumulate in various organs especially in joint tissue and do damage to the joint tissue during aging and diabetes. Synovial angiogenesis and inflammation are observed across the full range of OA severity. The signaling pathway of AGEs on vascular endothelial growth factor (VEGF) production and inflammatory responses in synoviocytes are still unclear. Here, we investigated the role of receptor for AGEs (RAGE) and the signaling pathway involved in AGEs‐induced VEGF production and inflammatory responses in human synoviocytes. Human synoviocytes were cultured and treated with AGEs (25–100 µg/ml). AGEs significantly induced the protein expressions of cyclooxygenase‐2 (COX‐2) and VEGF and the productions of prostaglandin‐E2 (PGE2), VEGF, interleukin‐6 (IL‐6), and metalloproteinase‐13 (MMP‐13) in human synoviocytes in a dose‐dependent manner. Moreover, AGEs markedly activated the phosphorylations of IκB kinase (IKK)α/β, IκBα, and nuclear factor (NF)‐κB‐p65 proteins in human synoviocytes in a time‐dependent manner. Treatment with neutralizing antibody for RAGE statistically significantly decreased the AGEs‐induced increase in COX‐2, VEGF, PGE2, IL‐6, and MMP13 and AGEs‐activated NF‐κB pathway activation. Taken together, these findings indicate that AGEs are capable of inducing VEGF production and inflammatory responses via RAGE‐NF‐κB pathway activation in human synoviocytes. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:791–800, 2016.