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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.


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.
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Figure 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.

Mentions: There is ample evidence that the transition from mPGES-1 to PGD synthase, with the subsequent synthesis of PGJ2-derived prostaglandins, is critical to initiating biochemical pathways associated with healing in OA (Fig. 3). As mentioned above, PPARγ-1 and -2 are part of a nuclear hormone superfamily. They derive from the same gene and produce slightly different proteins through alternative splicing of pre-mRNA with PPARγ-2 having 30 more amino acid residues at its amino terminus. It is the PPARγ-1 gene (up-regulated by osteoblast stretching (vide supra)) that is abundant in many tissues and immune cells. PPARγ-1 is expressed in human cartilage but is down regulated in OA. In articular chondrocytes, the gene is also down regulated by IL-1β [48]. 15d-PGJ2 was the first endogenous agonist of PPARγ to be identified [49, 50]. Also, 15d-PGJ2 completely suppressed NO and PGE2 production in human OA chondrocytes. COX-2 was slightly inhibited, but substantial COX-2 activity remained allowing for PGD2 synthesis during this anti-inflammatory phase [40, 51]. Finally, 15d-PGJ2 completely inhibits mPGES-1 in both human and rat OA chondrocytes thus abolishing PGE2 synthesis [34, 52, 53].


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

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Figure 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.
Mentions: There is ample evidence that the transition from mPGES-1 to PGD synthase, with the subsequent synthesis of PGJ2-derived prostaglandins, is critical to initiating biochemical pathways associated with healing in OA (Fig. 3). As mentioned above, PPARγ-1 and -2 are part of a nuclear hormone superfamily. They derive from the same gene and produce slightly different proteins through alternative splicing of pre-mRNA with PPARγ-2 having 30 more amino acid residues at its amino terminus. It is the PPARγ-1 gene (up-regulated by osteoblast stretching (vide supra)) that is abundant in many tissues and immune cells. PPARγ-1 is expressed in human cartilage but is down regulated in OA. In articular chondrocytes, the gene is also down regulated by IL-1β [48]. 15d-PGJ2 was the first endogenous agonist of PPARγ to be identified [49, 50]. Also, 15d-PGJ2 completely suppressed NO and PGE2 production in human OA chondrocytes. COX-2 was slightly inhibited, but substantial COX-2 activity remained allowing for PGD2 synthesis during this anti-inflammatory phase [40, 51]. Finally, 15d-PGJ2 completely inhibits mPGES-1 in both human and rat OA chondrocytes thus abolishing PGE2 synthesis [34, 52, 53].

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.