Abnormal loading mechanisms in OA (PTOA)
Inflammatory response
Inflammation contributes to Which cytokines are important in OA pathogenesis?
symptoms and progression of OA Interleukin-1 is thought to be important in OA pathogenesis
Overproduction of cytokines and To test this they stopped interleukin-1 binding from its
growth factors by the inflamed receptor, to stop the kickstart of the inflammatory processes
synovium and activated chondrocytes Dog model: ACL transection with intra-articular injection
is major mediator in OA of rIL-1 receptor antagonist
Substantial (elevated) quantities of Results: 2mg of rIL-1Ra - articular cartilage was a lot
inflammatory cytokines e.g. IL-1, IL- smoother than naïve and no osteophyte development, 4mg-
6, IL-15and TNFα are elevated in the better than naïve, but worse than 2mg
serum of OA patients Reason the high conc. Is worse, is because the body is
starting to react against the drug and is creating antibodies
This is evidence that IL-1 has some involvement in OA
How do these cytokines stimulate OA Caron et al. 1996
pathogenesis?
Major transcriptional circuit
implicated in inflammation is NFκB
Normally NFκB, is associated with an Involvement of Nitric Oxide signalling in OA pathogenesis
inhibitor, which stops it from acting as NO is important in body, but too much in cartilage is not
a transcription factor. good
When IL-1 binds to its receptor, it Cytokines induce production of nitric oxide (NO)
kicks starts a series of signalling Dog ACL transection model; assessed efficacy of selective
events, which breaks down the inhibitor of inducible NO synthase (iNOS): N-iminoethyl-
inhibitor and allows NFκB to move L-lysine (L-NIL)
into the nucleus and initiate So blocking NO and see what happens
downstream events Histology is not quite as good as control, but much better
than histology in OA
What happens when you stop NFκB Pelletier er al. 1998
signalling?
Rat model: medial collateral ligament Why is NO important in OA?
transection and partial meniscectomy L-NIL also reduced IL-1βand PGE2 levels (seen in OA
(giving them PTOA) patients)
Administered an intra-articular NO can increase expression of the enzymes that break
injection of Ad-siRNA NFκBp65 down cartilage/ collagenases (break down collagen (type
So, knocked out the NFκBp65 sub II)
unit, as NFκB can’t work with just In the study above, when you stop NO signalling, you
one sub unit reduce the expression of MMPs, especially MMPs in
Then looked at the cartilage overtime, cartilage
to see the effects of stopping NFκB If you block NO signalling, you block collagenases
signalling
Inhibition of NFκBp65 isn’t as good
as the control (without OA) but is Importance of MMP13 in OA pathogenesis
much better than OA. Organisation of MMP13 KO mice subjected to medial meniscal
articular cartilage can still be seen, destabilisation (Little et al. 2009)
whereas, in OA there is no Increase in structural damage in Wild Type tibia
organisation NNP13 Knock Out mice had an increased loss of aggrecan
If you block NFκB, you are also in early stages in femoral compartment, but stops the OA
stopping further production of from progressing
cytokines, such as MMPs Suggestive that:
This is further evidence of the early phases of OA are dominated by non-MMP13-
importance of cytokines in OA dependent events
pathogenesis, as cytokines are Preservation of cartilage structure in MMP13 KO mice
working through NFκB despite aggrecan loss
Chen et al. 2008 However, if you make a generic MMP inhibitor it’ll block MMP
elsewhere in body was found to cause cardiac failure
Inflammatory response
Inflammation contributes to Which cytokines are important in OA pathogenesis?
symptoms and progression of OA Interleukin-1 is thought to be important in OA pathogenesis
Overproduction of cytokines and To test this they stopped interleukin-1 binding from its
growth factors by the inflamed receptor, to stop the kickstart of the inflammatory processes
synovium and activated chondrocytes Dog model: ACL transection with intra-articular injection
is major mediator in OA of rIL-1 receptor antagonist
Substantial (elevated) quantities of Results: 2mg of rIL-1Ra - articular cartilage was a lot
inflammatory cytokines e.g. IL-1, IL- smoother than naïve and no osteophyte development, 4mg-
6, IL-15and TNFα are elevated in the better than naïve, but worse than 2mg
serum of OA patients Reason the high conc. Is worse, is because the body is
starting to react against the drug and is creating antibodies
This is evidence that IL-1 has some involvement in OA
How do these cytokines stimulate OA Caron et al. 1996
pathogenesis?
Major transcriptional circuit
implicated in inflammation is NFκB
Normally NFκB, is associated with an Involvement of Nitric Oxide signalling in OA pathogenesis
inhibitor, which stops it from acting as NO is important in body, but too much in cartilage is not
a transcription factor. good
When IL-1 binds to its receptor, it Cytokines induce production of nitric oxide (NO)
kicks starts a series of signalling Dog ACL transection model; assessed efficacy of selective
events, which breaks down the inhibitor of inducible NO synthase (iNOS): N-iminoethyl-
inhibitor and allows NFκB to move L-lysine (L-NIL)
into the nucleus and initiate So blocking NO and see what happens
downstream events Histology is not quite as good as control, but much better
than histology in OA
What happens when you stop NFκB Pelletier er al. 1998
signalling?
Rat model: medial collateral ligament Why is NO important in OA?
transection and partial meniscectomy L-NIL also reduced IL-1βand PGE2 levels (seen in OA
(giving them PTOA) patients)
Administered an intra-articular NO can increase expression of the enzymes that break
injection of Ad-siRNA NFκBp65 down cartilage/ collagenases (break down collagen (type
So, knocked out the NFκBp65 sub II)
unit, as NFκB can’t work with just In the study above, when you stop NO signalling, you
one sub unit reduce the expression of MMPs, especially MMPs in
Then looked at the cartilage overtime, cartilage
to see the effects of stopping NFκB If you block NO signalling, you block collagenases
signalling
Inhibition of NFκBp65 isn’t as good
as the control (without OA) but is Importance of MMP13 in OA pathogenesis
much better than OA. Organisation of MMP13 KO mice subjected to medial meniscal
articular cartilage can still be seen, destabilisation (Little et al. 2009)
whereas, in OA there is no Increase in structural damage in Wild Type tibia
organisation NNP13 Knock Out mice had an increased loss of aggrecan
If you block NFκB, you are also in early stages in femoral compartment, but stops the OA
stopping further production of from progressing
cytokines, such as MMPs Suggestive that:
This is further evidence of the early phases of OA are dominated by non-MMP13-
importance of cytokines in OA dependent events
pathogenesis, as cytokines are Preservation of cartilage structure in MMP13 KO mice
working through NFκB despite aggrecan loss
Chen et al. 2008 However, if you make a generic MMP inhibitor it’ll block MMP
elsewhere in body was found to cause cardiac failure
