PPARgamma and PPARdelta agonists downregulate interleukin-1-stimulated inflammatory responses in human chondrocytes

EL Paukkeri1, M Hämäläinen1, T Moilanen2, E Moilanen1. 1The Immunopharmacology Research Group, University of Tampere School of Medicine and Tampere University Hospital, Tampere, Finland, 2Coxa Hospital for Joint Replacement, Tampere, Finland

Introduction: Peroxisome proliferator-activated receptor (PPAR) agonists have been used as a pharmacological treatment of obesity-linked diseases for several years. Their effects on energy metabolism have been widely described, but in recent studies they have also been found to modulate inflammatory responses. Inflammatory cytokine induced matrix metalloproteinase (MMP) production and impaired metabolism of tissue cells have been suggested to account for cartilage degradation in arthritis. In the present study we investigated the effects of PPAR agonists on interleukin-1 (IL-1) stimulated inflammatory responses and MMP production in human chondrocytes.

Methods: The effects of PPAR agonists on IL-1 stimulated responses were investigated both in primary chondrocytes and in human T/C28a chondrocyte cell line. Primary chondrocytes were isolated by enzyme digestion from leftover pieces of cartilage obtained during total knee replacement surgery of osteoarthritic patients. After 24 hours incubation with vehicle or IL-1 (100 pg/ml) and GW1929 (100 µM), GW0742 (100 µM), muraglitazar (30 µM in T/C28a cells and 100 µM in primary chondrocytes) or fenofibrate (100 µM), culture medium was collected for further analysis. The levels of IL-6, MMP1 and MMP3 were determined by ELISA. Nitric oxide (NO) production was investigated by measuring its stabile metabolite nitrite in culture medium by Griess method.

Results: PPARgamma agonist GW1929, PPARdelta agonist GW0742 and PPARgamma/alpha dual agonist muraglitazar decreased NO production (-29%, -16% and -33 %, respectively, p<0.01) in IL-1 stimulated human primary chondrocytes. Muraglitazar and GW0742, but not GW1929, also reduced the production of IL-6 by 56 % and 65 % (p<0.01) in primary chondrocytes. MMP1 levels were decreased by muraglitazar both in primary chondrocytes (-43%, p<0.05) and in T/C28a cells (-57 %, p<0.01) while the effects of GW0742 and GW1929 on MMP1 production were slighter. The effects of all the agonists on the production of MMP3 were minor. As distinct from the PPARgamma and PPARdelta agonists, PPARalpha agonist fenofibrate did not clearly modulate either NO or IL-6 production. Interestingly, fenofibrate evidently increased the levels of MMP1 both in primary chondrocytes (+126%, p<0.01) and in T/C28a cells (+120 %, p<0.01) as well as MMP3 production in T/C28a cells (+120%, p<0.01).

Conclusions: The present results show that PPARgamma and PPARdelta agonists attenuate IL-1 induced inflammatory responses in chondrocytes and have a minor inhibitory effect on the production of MMPs. However, PPARalpha agonist did not share these effects. The results suggest that PPARgamma and PPARdelta agonism might be a beneficial feature of pharmacological agents in the treatment of chronic arthritis.