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.
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Ying-Ju
YJ
Chen
Department of Geriatrics and Gerontology, National Taiwan University Hospital, Taipei, Taiwan.
Ding-Cheng
DC
Chan
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Chih-Kang
CK
Chiang
Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.
Ching-Chia
CC
Wang
Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan.
Ting-Hua
TH
Yang
Department of Emergency Medicine, National Defense Medical Center, Tri-Service General Hospital, Taipei, Taiwan.
Kuo-Cheng
KC
Lan
Department of Surgery, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan.
Sung-Chuan
SC
Chao
Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
Keh-Sung
KS
Tsai
Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan.
Rong-Sen
RS
Yang
Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Shing-Hwa
SH
Liu
D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D015398:Signal Transduction; D000070918:Synoviocytes / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D017127:Glycation End Products, Advanced; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D015232:Dinoprostone
advanced glycation end products (AGEs); osteoarthritis; receptor for AGEs (RAGE); synoviocytes; vascular endothelial growth factor