In this research line knowledge of cartilage is combined with clinical use of non-steroidal anti-inflammatory drugs (NSAIDs). While studies on the direct effects of NSAIDs on cartilage in vitro are numerous, but far from conclusive, studies on the second generation NSAIDs, the frequently used selective COX-2 inhibitors (COXIBs), are scarce. We try to gain more insight in the direct effects of selective COX-2 inhibitors on cartilage, by using a combination of human in vitro studies, animal in vivo studies and clinical studies . An issue of major relevance to clinical practice since it is essential that in case of prolonged use as is the case in osteoarthritis, treatment does not hamper intrinsic cartrilage repair activity.
Upregulation of COX-2 by autocrine and paracrine produced mediators such as IL-1β/TNFα (1). Concomitant upregulation of the EP receptors via COX-2 or other mechanisms (2).COX-2 upregulation results in large concentrations of prostaglandin-E2 (3). Autocrine and parcrine stimulation of the EP4 receptor by prostaglandin-E2 (4). This results in increased proteoglycan release (5). IL-1β/TNFα induces simultaneous activation of iNOS (6), which leads to formation of nitric oxide (7). This results among other effects, in a decreased proteoglycan synthesis (8) and may stimulate COX-2 production (9) concomitantly leading to enhanced release. The disturbance of proteoglycan synthesis and proteoglycan release will result in further loss of proteoglycan content (10) and with that to loss of cartilage matrix integrity. Selective COX-2 inhibition by celecoxib, amongst others, leads to inhibition of the COX-2 pathway and with that prostaglandin-E2 production. This results in normalization of proteoglycan release, but not synthesis.
At this moment we are further studying the role of COX-2 and the effects of COX-2 inhibition in osteoarthritis. With this research we are trying to prove “disease modifying” characteristics of selective COX-2 inhibitors
For more information contact Dr Simon Mastbergen (email: S.Mastbergen@umcutrecht.nl)