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A little game – What the hell is this thing? Take a guess in the comments below – the red blobs are me deleting labels that might have given it away.
The prize is kudos, the admiration of your peers, and a life time subscription to this blog. 😉
Friday Night (12th)
- 21:43-21:48 – “Incredibly Bright” – cloud cover 23%
Saturday Night (13th)
- 20:52-20:59 – “Incredibly Bright” – cloud cover 99% 😦
- 22:29-22:32 – “Incredibly Bright / Short pass” – cloud cover 100% 😦
Sunday Night (14th) (for the stragglers)
- 21:39-21:44 – “Incredibly Bright” – cloud cover 94% 😦
So… Friday night it is then, caveats about weather forecasting notwithstanding. If we can drag ourselves out of the bar for 5 minutes.
In a little experiment, I’m going to do a journal club style blog post. I’m going to look at a paper, explain why I like it, and how I think it could be improved. If you like it, “like it” and I may do more.
The paper I am going to look at is “Identification of a central role for complement in osteoarthritis” by Wang et al, published in Nature Medicine in December 2011. [PUBMED|PDF|F1000] I chose this because it is a pretty big paper in my field, and it is a damn good paper (but it is not without flaws).
The paper explores the hypothesis that the complement immune system is involved in the development of osteoarthritis (OA) (a degenerative disease of our joints).
The authors show that the presence of markers of complement activation in samples from (human) patients, such as “C3a des arg” and “C5b-9” (the membrane attack complex), correlate with osteoarthritis (fig1 b&c).
The membrane attack complex (or MAC) is the final step of the complement immune cascade, and is a complex of proteins that in high levels punches holes in cells and kills them.
They also show that patients with osteoarthritis make more complement activating proteins and less complement inhibiting protein in the synovium of their joints when compared to healthy patients (fig1 e).
Having demonstrated a correlation between complement activation and osteoarthritis in human samples, Wang et al go on to explore this in mouse models of arthritis.
They show that if you knockout the genes for complement components C5 and C6 in mice (preventing the formation of the MAC), these mice develop less severe arthritis (as measured by cartilage degradation) in surgically-induced arthritis (fig2).
The also show that in mice lacking CD59, a natural inhibitor of complement, cartilage degradation is more severe.
These genetic models support the authors’ hypothesis that complement activation might enhance osteoarthritis progression/severity.
They then show in human chondrocytes (cartilage producing cells)(in cell culture) that extracts of arthritic cartilage or certain proteins (such as fibromodulin) known to be over-produced in arthritis can induce the production of the MAC.
And they show that low (“sub-lytic”) levels of MAC can make normal chondrocytes (but not C5 deficient chondrocytes) produce proteins known to degrade cartilage, such as ADAMTS-4 and -5, but also some Matrix MetalloProteases (MMPs).
Again, this observation supports the hypothesis that complement activation (that culminates in MAC formation) can induce osteoarthritis.
All in all, a very comprehensive paper, and a fantastic piece of work, and I’ve deliberately ignored some parts of the paper to simplify the story.
There are however, a few chinks in the armour.
1) All mice models of arthritis were surgical models – i.e surgery was performed on the mice that caused them to develop arthritis. No “sham-surgery” controls were performed (or if they were, they weren’t mentioned, which seems odd).
Given that it is known that surgery can induce complement activation, this control absolutely should have been done.
Other models of arthritis (such as proteoglycan induced arthritis) were not explored.
2) They should have looked for the products of ADAMTS induced cartilage degradation in the arthritis mice. Antibodies that recognise the breakdown products (so-called “NITEGE”) are available and could be used in immuno-histochemistry to see if/where ADAMTS-mediated cartilage damage is occurring. (H/T to Jen in our lab who pointed this out).
3) None of the subjective cartilage degradation scoring was blinded. This is a potential source of bias.
I still think that the hypothesis explored in this paper is a good one, and that complement activation is almost certainly part of the complicated puzzle of osteoarthritis pathology, but ideally I’d like to see a follow-up paper that included some of these extra experiments.