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Inflammatory Pathways in Knee Osteoarthritis: Potential Targets for Treatment

View Article: PubMed Central

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.

No MeSH data available.


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.
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Figure 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.

Mentions: The downstream effects of the pro-inflammatory prostaglandins released in OA should also be taken into account. One of the first effects of pro-inflammatory cytokines is the activation of phospholipase A2 (PLA2) which cleaves cellular membranes thereby liberating arachidonic acid (Fig. 2). PLA2 consists of three broad classes of enzymes, each of which has subclasses that may be regulated during the course of inflammation and recovery [33]. Also induced by pro-inflammatory cytokines is cyclo-oxygense 2 (COX-2). COX-2 is highly up-regulated during inflammation and catalyzes the conversion of arachidonic acid into PGH2 (Fig. 2). PGH2 is the precursor to many eicosanoids (such as prostacyclin and thromboxane), but special emphasis will be placed on just two of these, PGE2 and PGD2 (Fig. 2). The former is the major pro-inflammatory prostaglandin, and the latter is the precursor to the prostaglandins associated with recovery. PGD2 halts and reverses the inflammatory response in a multitude of experimental systems.


Inflammatory Pathways in Knee Osteoarthritis: Potential Targets for Treatment
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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4997945&req=5

Figure 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.
Mentions: The downstream effects of the pro-inflammatory prostaglandins released in OA should also be taken into account. One of the first effects of pro-inflammatory cytokines is the activation of phospholipase A2 (PLA2) which cleaves cellular membranes thereby liberating arachidonic acid (Fig. 2). PLA2 consists of three broad classes of enzymes, each of which has subclasses that may be regulated during the course of inflammation and recovery [33]. Also induced by pro-inflammatory cytokines is cyclo-oxygense 2 (COX-2). COX-2 is highly up-regulated during inflammation and catalyzes the conversion of arachidonic acid into PGH2 (Fig. 2). PGH2 is the precursor to many eicosanoids (such as prostacyclin and thromboxane), but special emphasis will be placed on just two of these, PGE2 and PGD2 (Fig. 2). The former is the major pro-inflammatory prostaglandin, and the latter is the precursor to the prostaglandins associated with recovery. PGD2 halts and reverses the inflammatory response in a multitude of experimental systems.

View Article: PubMed Central

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.

No MeSH data available.