Project

Discipline

osteoarthritis; IL-6; reactive oxygen species; xanthine oxidoreductase

Lead
Les dépôts des cristaux calciques autour les articulations arthrosiques sont fréquents, mais leur rôle dans la pathogenèse de l’arthrose est méconnu. La recherche que nous proposons essaie de répondre à cette question, en utilisant une combinaison d’approches différentes, à la recherche des nouveaux traitements pour cette maladie.
Lay summary
L’arthrose est une maladie répandue pour laquelle les traitements efficaces n’existent pas, à part la chirurgie lorsque l’atteinte est très avancée. Grace au soutien précèdent du FNS, nous avons trouvé que les cristaux calciques aient un effet nocif sur les structures articulaires, notamment le cartilage et la membrane synoviale. Le but de notre projet est d’identifier les mécanismes responsables et de rechercher les moyens efficaces de les inhiber. Les différentes approches expérimentales incluent les modèles expérimentaux chez la souris, les tissus articulaires issus des patients arthrosiques ainsi que les analyses biochimiques et moléculaires des cellules en culture. Par ces expériences, nous recherchons les nouvelles cibles thérapeutiques qui pourraient être appliqué au traitement des malades souffrant de l’arthrose.

Direct link to Lay Summary

Last update: 02.04.2014

Active participation

Title	Year

Number	Title	Start	Funding scheme

Osteoarthritis (OA) is the most prevalent joint disease in man and its pathophysiology is only partly understood. Cartilage degradation is a key process in the development of OA. Our current treatments are essentially symptomatic, and there are no therapies that have been shown to inhibit OA progression effectively. Experimental studies (including results obtained from our laboratory) suggest that calcium crystal deposition (of basic calcium phosphate and of calcium pyrophosphate) result in calcification of joint structures such as cartilage and the synovial membrane and can be initiating or progression factors in OA, and in experimental studies, preceded cartilage degradation. We have shown in our laboratory that chondrocytes stimulated by calcium crystals induced IL6 production, a cytokine that could be involved in cartilage breakdown. Moreover, we obtained evidence that implicate chondrocyte xanthine oxidoreductase (XOR) activity in this process. The xanthine oxidase (XO) form of XOR enzyme is induced during inflammation and generates ROS that can act on intracellular signalling. Our major working hypothesis is that calcium crystal-induced IL-6 production depends on XO-generated ROS and that IL-6 drives OA induction/progression.In this proposal, we plan to study these pathways in greater detail, using murine chondrocytes and human cartilage explant culture systems to investigate the mechanisms that mediate the crystal effect on cartilage as well as studying the development of OA in vivo, using a murine model of mechanically induced OA. We will focus firstly on the mechanisms by which crystals induce IL6 secretion from chondrocytes and test if inhibition of IL6 signalling will impact of OA development. Secondly we will investigate if XOR production of ROS is implicated in OA. This will be tested in chondrocyte and cartilage culture systems and in the in vivo OA model, using XO inhibitors as well as transgenic “knockin” mice expressing only the oxidase or reductase form of XOR. The understanding of the roles of IL6 and XOR in cartilage metabolism may open new avenues in the prevention or treatment of OA in man.