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
Authors: Keh Sung Tsai
Rong Sen Yang
Ying Ju Chen
Shing Hwa Liu
Meei Ling Sheu
Journal: PLoS ONE (2013)
Discipline: Multidisciplinary
Keywords: AGEs; osteoarthritis; chondrocytes; PPARγ; TLR4
Affiliations: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.

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. 

Retracted: No

PubPeer comments:
 Reported to the journal in 2015. * Red boxes: The alpha-tubulin panels of Figures 2B, 2C, 2D, 3A, 3B, 5A, 5D appear to look identical while they represent at least 2 different experiments (time series vs concentration series). * Blue boxes: The alpha-tubulin panels of Figures 5B and 5C appear to look identical while they represent 2 different experiments (time series vs concentration series). * Purple boxes: The beta-actin panels of Figure 7C and 7D appear to look identical while they represent 2 different experiments ![file] , 
 #1 Dear Sir Madam, Thank you for comments, we are very sorry for such misplantation of internal control figures, we will repeat these experiments immediately and make corrections to the Journal. Sincerely yours, The authors ,