Inflammatory Pathways in Knee Osteoarthritis: Potential Targets for Treatment

Abstract

Osteoarthritis (OA) of the knee is a wide-spread, debilitating disease that is prominent in Western countries. It is associated with old age, obesity, and mechanical stress on the knee joint. By examining the recent literature on the effect of the anti-inflammatory prostaglandins 15d-PGJ2 and Δ12-PGJ2, we propose that new therapeutic agents for this disease could facilitate the transition from the COX-2-dependent pro-inflammatory synthesis of the prostaglandin PGE2 (catalyzed by mPGES-1), to the equally COX-2-dependent synthesis of the aforementioned anti-inflammatory prostaglandins. This transition could be instrumental in halting the breakdown of cartilage via matrix metalloproteinases (MMPs) and aggrecanases, as well as promoting the matrix regeneration and synthesis of cartilage by chondrocytes. Another desirable property of new OA therapeutics could involve the recruitment of mesenchymal stem cells to the damaged cartilage and bone, possibly resulting in the generation of chondrocytes, synoviocytes, and, in the case of bone, osteoblasts. Moreover, we propose that research promoting this transition from pro-inflammatory to anti-inflammatory prostaglandins could aid in the identification of new OA therapeutics.

Keywords: Cartilage; cyclo-oxygenase; inflammation; knee osteoarthritis; prostaglandins; synovial fluid.

Fig. (1)

Zonal arrangement of joint cartilage. This schematic diagram shows the top superficial layers and the deep bottom layers. Underneath the synovial membrane, the articular cartilage is actually composed of three main zones: the superficial, the middle, and the deep layers, with the deep layer abutting the tidal line. The three layers of articular cartilage have different physical and biochemical properties (discussed within the text). Underneath the cement line is subchondral bone, which is implicated in the progression of OA and is thought to be the source of mesenchymal stem cells (MSCs). MSCs can migrate into the cartilage layers in the presence of certain stimuli.

Fig. (2)

Prostaglandin synthesis pathways. Following the activation of PLA2 by pro-inflammatory cytokines, arachidonic acid is liberated from cellular membranes. COX-1 and COX-2 convert arachidonic acid to the unstable prostaglandin PGH₂. PGH₂ can be converted to the pro-inflammatory prostaglandin PGE₂ by mPGES-1 or converted to PGD₂, a prostaglandin with well-known anti-inflammatory effects. These effects are mostly due to further non-enzymatic conversions of PGD₂ to PGJ₂ and then 15d-PGJ₂. Intriguingly, PGJ₂ can also convert to Δ12-PGJ₂ in the presence of albumin.

Fig. (3)

Schematic representation of the effect of 15d-PGJ₂. 15d-PGJ₂ has a number of pathways by which it initiates an anti-inflammatory cascade. It can react with the PGD₂ receptors (DP₁ and DP₂) to stimulate cyclic AMP (cAMP) production and increase protein kinase A (PKA) leading to downstream anti-inflammatory effects. More importantly, 15d-PGJ₂ can enter the cell directly and activate PPARγ resulting in the transcription of multiple anti-inflammatory mRNAs. Additionally, PPARγ inhibits the transcription factor NF-κB by binding to the inhibitor IκB thus protecting IκB degradation by IκB kinase (IKK). Finally, 15d-PGJ₂ can also inhibit IKK activity through possible covalent modification and, further downstream, can inhibit NF-κB nuclear translocation as well as impairing NF-κB binding to DNA.