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.
Highlights
Osteoarthritis (OA) is a progressive degenerative joint disease with signs and symptoms of inflammation, including joint pain, swelling, and stiffness leading to significant functional impairment and disability in older adults [1]
These results indicate that Advanced glycation end products (AGEs) are capable of inducing inflammatory signalings and reducing collagen II expression in human OA chondrocytes
Several studies have found that peroxisome proliferatoractivated receptor c (PPARc) agonists can reduce the expression and synthesis of cartilage degradation products in vitro and in vivo, and suggested that activation of PPARc is capable of reducing the progression of OA [22,20,27,32]
Summary
Osteoarthritis (OA) is a progressive degenerative joint disease with signs and symptoms of inflammation, including joint pain, swelling, and stiffness leading to significant functional impairment and disability in older adults [1]. Catabolic activities of OA chondrocytes are related to the elevated release of cartilage degrading enzymes, such as matrix metalloproteinases (MMPs), while anabolic activities result in the productions of type II collagen and aggrecan [2]. Accumulation of AGEs in cartilage chondrocytes shows the decreased proteoglycan and collagen synthesis, which leads to stiffness and brittleness of the articular cartilage [7]. AGEs can up-regulate the production of MMPs that mediate cartilage degradation leading to the joint destruction [8]. Activation of mitogen-activated protein kinase (MAPK)-regulated NF-kB signaling was involved in this AGEs/ RAGE-induced expressions of IL-6 and IL-8 in chondrocytes [9]. The role of TLR4 and RAGE in AGEs-induced inflammatory signalings in human chondrocytes remains to be clarified
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