title: Advanced glycation end products induce peroxisome proliferator-activated receptor γ down-regulation-related inflammatory signals in human chondrocytes via Toll-like receptor-4 and receptor for advanced glycation end products.
abstract: Accumulation of advanced glycation end products (AGEs) in joints is important in the development of cartilage destruction and damage in age-related osteoarthritis (OA). The aim of this study was to investigate the roles of peroxisome proliferator-activated receptor γ (PPARγ), toll-like receptor 4 (TLR4), and receptor for AGEs (RAGE) in AGEs-induced inflammatory signalings in human OA chondrocytes. Human articular chondrocytes were isolated and cultured. The productions of metalloproteinase-13 and interleukin-6 were quantified using the specific ELISA kits. The expressions of related signaling proteins were determined by Western blotting. Our results showed that AGEs enhanced the productions of interleukin-6 and metalloproteinase-13 and the expressions of cyclooxygenase-2 and high-mobility group protein B1 and resulted in the reduction of collagen II expression in human OA chondrocytes. AGEs could also activate nuclear factor (NF)-κB activation. Stimulation of human OA chondrocytes with AGEs significantly induced the up-regulation of TLR4 and RAGE expressions and the down-regulation of PPARγ expression in a time- and concentration-dependent manner. Neutralizing antibodies of TLR4 and RAGE effectively reversed the AGEs-induced inflammatory signalings and PPARγ down-regulation. PPARγ agonist pioglitazone could also reverse the AGEs-increased inflammatory signalings. Specific inhibitors for p38 mitogen-activated protein kinases, c-Jun N-terminal kinase and NF-κB suppressed AGEs-induced PPARγ down-regulation and reduction of collagen II expression. Taken together, these findings suggest that AGEs induce PPARγ down-regulation-mediated inflammatory signalings and reduction of collagen II expression in human OA chondrocytes via TLR4 and RAGE, which may play a crucial role in the development of osteoarthritis pathogenesis induced by AGEs accumulation.
authors.affiliation: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ying Ju
authors.initials: YJ
authors.lastname: Chen
authors.forename: Meei Ling
authors.initials: ML
authors.lastname: Sheu
authors.forename: Keh Sung
authors.initials: KS
authors.lastname: Tsai
authors.forename: Rong Sen
authors.initials: RS
authors.lastname: Yang
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000704:Analysis of Variance; D015153:Blotting, Western; D019902:Chondrocytes / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D010003:Osteoarthritis / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D015850:Interleukin-6; D047495:PPAR gamma; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003094:Collagen; D051546:Cyclooxygenase 2; D053509:Matrix Metalloproteinase 13