Objective: Advanced glycation end products (AGEs) play a pivotal role in the initiation and progression of osteoarthritis (OA). Peroxisome proliferator-activated receptor-G (PPARG) has been shown to exhibit anti-inflammatory and anticatabolic properties and to be protective in animal models of OA. This study was aimed to investigate the possible protective effect of the PPARG agonist pioglitazone on AGE-induced chondrocyte damage. Methods: Cultured chondrocytes were stimulated with AGEs in the presence or absence of an antibody against the receptor for AGEs (anti-RAGE), an inhibitor of NF-TB (pyrrolidine dithiocarbamate) and pioglitazone. The RNA expression levels of TNF-E, matrix metalloproteinase (MMP)-13 and PPARG were detected by RT-PCR. The expression of nuclear p65 was determined by Western blot analysis. Results: Upregulation of TNF-E and MMP-13 as well as downregulation of PPARG were induced by AGEs in a time- and dose-dependent manner. The maximum effect was induced by 100 Vg/ml AGEs. This effect can be inhibited by anti-RAGE. Pioglitazone dose-dependently inhibited the expression of TNF-E and MMP-13 induced by AGEs, which was combined with the inhibition of nuclear p65 expression. Conclusion: The PPARG agonist pioglitazone modulates TNF-E and MMP-13 expression in cultured rabbit chondrocytes via NF-TB signaling. It indicates that pioglitazone may have therapeutic potential in OA. i 2014 S. Karger AG, Basel

Keywords:
Advanced glycation end products, Peroxisome proliferator-activated receptor-γ, Chondrocyte, Pioglitazone, Tumor necrosis factor-α, Matrix metalloproteinase-13
1.
Holt I, Cooper RG, Hopkins SJ: Relationships between local inflammation, interleukin-6 concentration and the acute phase protein response in arthritis patients. Eur J Clin Invest 1991;21:479-484.
2.
Lawrence RC, Helmick CG, Arnett FC, et al: Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-799.
3.
Goldring MB, Goldring SR: Osteoarthritis. J Cell Physiol 2007;213:626-634.
4.
Feydy A, Pluot E, Guerini H, Drape JL: Osteoarthritis of the wrist and hand, and spine. Radiol Clin North Am 2009;47:723-759.
5.
Creamer P, Hochberg MC: Osteoarthritis. Lancet 1997;350:503-508.
6.
Felson DT, Zhang Y: An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 1998;41:1343-1355.
7.
Felson DT, Lawrence RC, Dieppe PA, et al: Osteoarthritis: new insights. Part 1. The disease and its risk factors. Ann Intern Med 2000;133:635-646.
8.
Schmidt AM, Yan SD, Stern DM: The dark side of glucose. Nat Med 1995;1:1002-1004.
9.
Reiser KM: Nonenzymatic glycation of collagen in aging and diabetes. Proc Soc Exp Biol Med 1998;218:23-37.
10.
DeGroot J, Verzijl N, Wenting-van WMJ, et al: Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis. Arthritis Rheum 2004;50:1207-1215.
11.
Chen JR, Takahashi M, Suzuki M, Kushida K, Miyamoto S, Inoue T: Comparison of the concentrations of pentosidine in the synovial fluid, serum and urine of patients with rheumatoid arthritis and osteoarthritis. Rheumatology (Oxford) 1999;38:1275-1278.
12.
Rasheed Z, Akhtar N, Haqqi TM: Advanced glycation end products induce the expression of interleukin-6 and interleukin-8 by receptor for advanced glycation end product-mediated activation of mitogen-activated protein kinases and nuclear factor-TB in human osteoarthritis chondrocytes. Rheumatology (Oxford) 2011;50:838-851.
13.
Cecil DL, Johnson K, Rediske J, Lotz M, Schmidt AM, Terkeltaub R: Inflammation-induced chondrocyte hypertrophy is driven by receptor for advanced glycation end products. J Immunol 2005;175:8296-8302.
14.
Yan SD, Schmidt AM, Anderson GM, et al: Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem 1994;269:9889-9897.
15.
Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM: Activation of the receptor for advanced glycation end products triggers a p21ras-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 1997;272:17810-17814.
16.
Yammani RR, Carlson CS, Bresnick AR, Loeser RF: Increase in production of matrix metalloproteinase 13 by human articular chondrocytes due to stimulation with S100A4: role of the receptor for advanced glycation end products. Arthritis Rheum 2006;54:2901-2911.
17.
Nah SS, Choi IY, Yoo B, Kim YG, Moon HB, Lee CK: Advanced glycation end products increases matrix metalloproteinase-1, -3, and -13, and TNF-E in human osteoarthritic chondrocytes. FEBS Lett 2007;581:1928-1932.
18.
Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W: Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology 1996;137:354-366.
19.
Fahmi H, Pelletier JP, Martel-Pelletier J: PPARG ligands as modulators of inflammatory and catabolic responses in arthritis. An overview. J Rheumatol 2002;29:3-14.
20.
Barish GD, Narkar VA, Evans RM: PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590-597.
21.
Bordji K, Grillasca JP, Gouze JN, et al: Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) E and G and retinoid Z receptor in cartilage. PPARG activation modulates the effects of interleukin-1F on rat chondrocytes. J Biol Chem 2000;275:12243-12250.
22.
Fahmi H, Di Battista JA, Pelletier JP, Mineau F, Ranger P, Martel-Pelletier J: Peroxisome proliferator-activated receptor G activators inhibit interleukin-1F-induced nitric oxide and matrix metalloproteinase 13 production in human chondrocytes. Arthritis Rheum 2001;44:595-607.
23.
Kobayashi T, Notoya K, Naito T, et al: Pioglitazone, a peroxisome proliferator-activated receptor G agonist, reduces the progression of experimental osteoarthritis in guinea pigs. Arthritis Rheum 2005;52:479-487.
24.
Yang Q, Chen C, Wu S, Zhang Y, Mao X, Wang W: Advanced glycation end products downregulates peroxisome proliferator-activated receptor G expression in cultured rabbit chondrocyte through MAPK pathway. Eur J Pharmacol 2010;649:108-114.
25.
Valencia JV, Weldon SC, Quinn D, et al: Advanced glycation end product ligands for the receptor for advanced glycation end products: biochemical characterization and formation kinetics. Anal Biochem 2004;324:68-78.
26.
Corvol MT, Dumontier MF, Rappaport R: Culture of chondrocytes from the proliferative zone of epiphyseal growth plate cartilage from prepubertal rabbits. Biomedicine 1975;23:103-107.
27.
Steenvoorden MM, Huizinga TW, Verzijl N, et al: Activation of receptor for advanced glycation end products in osteoarthritis leads to increased stimulation of chondrocytes and synoviocytes. Arthritis Rheum 2006;54:253-263.
28.
Fran1ois M, Richette P, Tsagris L, et al: Peroxisome proliferator-activated receptor-G down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element. J Biol Chem 2004;279:28411-28418.
29.
Fahmi H, Pelletier JP, Di Battista JA, Cheung HS, Fernandes JC, Martel-Pelletier J: Peroxisome proliferator-activated receptor G activators inhibit MMP-1 production in human synovial fibroblasts likely by reducing the binding of the activator protein 1. Osteoarthritis Cartilage 2002;10:100-108.
30.
Guglielmotto M, Aragno M, Tamagno E, et al: AGEs/RAGE complex upregulates BACE1 via NF-TB pathway activation. Neurobiol Aging 2012;33:196.e13-e27.
31.
Loeser RF, Yammani RR, Carlson CS, et al: Articular chondrocytes express the receptor for advanced glycation end products: potential role in osteoarthritis. Arthritis Rheum 2005;52:2376-2385.
© 2014 S. Karger AG, Basel
2014
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