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

PLoS One. 2013 Jun 12;8(6):e66611. doi: 10.1371/journal.pone.0066611. Print 2013.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Blotting, Western
  • Chondrocytes / metabolism*
  • Collagen / metabolism
  • Cyclooxygenase 2 / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / physiology*
  • Glycation End Products, Advanced / metabolism*
  • HMGB1 Protein / metabolism
  • Humans
  • Interleukin-6 / metabolism
  • Matrix Metalloproteinase 13 / metabolism
  • Osteoarthritis / metabolism*
  • PPAR gamma / metabolism*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / metabolism*
  • Toll-Like Receptor 4 / metabolism*


  • Glycation End Products, Advanced
  • HMGB1 Protein
  • Interleukin-6
  • PPAR gamma
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Collagen
  • Cyclooxygenase 2
  • Matrix Metalloproteinase 13

Grant support

This study was supported by the grant from the National Science Council of Taiwan (NSC97-2314-B-002-052-MY3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.