Rheumatoid Arthritis and the Cell Cycle

Jun 28 2010 Published by under Health Care/Medicine

This is a paper in which Sci has a certain amount of personal investment. You see, Sci has a family member who suffers from rheumatoid arthritis. And when I say suffer, I mean she suffers terribly. Rheumatoid arthritis is an autoimmune disease where you own body attacks the lining of the membranes between your joints. The result is painful swelling and stiffness (arthritis) which usually affects the smaller joints first (like your fingers) and which can severely impair your quality of life. Symptoms can wax and wane, but right now there is no cure, and treatments (which include things like aspirin or harder pain killers, steroids, and other immunosuppressants) are often not very effective and have a large number of side effects.
About 1% of the population is affected, and while the disease isn't itself fatal, it does shorten your lifespan by about 5-10 years, and seriously affects quality of life. Sufferers of rheumatoid arthritis often can't work and daily living is often impaired. So even though it's not a large population of people, it's still very important to find better treatments and attempt to find a cure to improve the lives of those who suffer from the disease.
And so this paper looks at two different proteins that might be able to help the disease...by controlling cell division. In fact, one of them is the SAME protein that Sci wrote about a few weeks ago when she looked at the incredible healing mouse. Interestingly, that mouse apparently is used for some autoimmune disease studies like lupus. Hmmmm.
ResearchBlogging.org Nasu et al. "Adenoviral transfer of cyclin-dependent kinase inhibitory genes suppresses collagen induced arthritis in mice" Journal of Immunology, 2000.
(Does anyone else always worry they are spelling "arthritis" wrong? It's one of those words that look wrong if you look at it too long)
Anyway, let me introduce to you...the arthritic mouse:
(ok, they don't really look like that, but it's cute!)

Above you can see a regular mouse paw on the left, and on the right you can see an arthritic mouse paw. This is a condition that is induced in the mice by injecting them with another animal's collagen. If you inject collagen at the base of a mouse's tail (not much is needed), the mouse will end up with an immune reaction to collagen in its joints, an immune reaction which resembles in almost every way rheumatoid arthritis. This obviously isn't fun for the mice, but it's very good for the research, because the arthritis develops in all four limbs, and so you can then do local injections of what you want to test into each limb, and check it against the rest to see how it's doing, which means you can do a lot with very few mice.
And now, let's talk talk about cell cycle inhibitors.
This is the cell cycle:

(For more on the cell cycle and mitosis, you can see a post I wrote on it here.)
You can see that at each stage of the cell cycle, there's a stopping point. At each stopping point, there is an important role for proteins that are called "cyclin-dependent kinases". These proteins determine whether or not a cell can go forward in the cell cycle, and thus whether or not the cell can eventually divide. The two we are concerned about here are p16 and p21. Both of these proteins inhibit the cell cycle from going forward. So if you have low p16 or p21, the cell cycle can go forward, while if you have high levels of p16 or p21, the cell cycle is stopped. We're gonna repeat that one more time:
p21 and p16 DOWN = cell cycle partay
p21 and p16 UP = NO MITOSIS FOR YOU
Now interestingly, the symptoms of rheumatoid arthritis involve a lot of cell division within the synovial tissues of the joints. What studies into rheumatoid arthritis have found is that the cells in the synovial tissue of people with rheumatoid arthritis have almost NO p16 or p21! And we recall (up there) that LOW p21 and p16 means a cell cycle partay. This cell cycle jammin' contributes a lot to the severe swelling and inflammation of the joints, and thus causes a whole bunch of the pain that people with rheumatoid arthritic experience. So the scientists had the idea that if you induced p16 or p21 in the arthritic mice in their joints, you might be able to STOP the cell cycle party, and reduce the inflammation and pain in the mice.
But how do you induce a cell cycle protein? Well now it's time to talk about adenoviral gene transfer.
Yeah, I know those words sound complicated, but it's not that bad. We'll start with a virus.

This is herpes. Everyone say hello to herpes! *waves*
So very basically, you take a virus (herpes and HIV are popular ones for this, you will see why). A virus is very good at what it does, and what it does it this: it's a packet of proteins with DNA or RNA inside. When it hits the right kind of cell, it latches on, drills in, and injects its packet of RNA or DNA into the cell. This RNA or DNA then HIJACKS the cell, using its proteins and stuff to pump out more viruses.
Of course, the practical upshot of this is that it makes you sick. But ever since we figured out we could use viruses as vectors, they have proved to be quite a boon to scientists.
This is because the virus will inject whatever DNA is in there. If you take OUT the virus' DNA, and put IN some DNA that you WANT, then that is what gets injected! In the case of adenoviruses, you can take out part of the DNA, and put in the DNA for, say, p21. Then when you administer the virus, the tissues it infects will make more p21. Viruses have their good sides.
You might ask, why herpes and HIV? Well, both of these viruses are particularly good at not getting recognized and rejected by the host immune system, so they sneak in and deposit the DNA without getting caught.
And now, back to the paper.
So they took viruses containing either p16 or p21, and locally injected them into the arthritic mice's limbs. They then looked at the amount of inflammation in the limbs. They did this first WITH the induction of arthritis, but they ALSO did it after the arthritis had already developed.

And here's what they got. You can see on the left panels when the mice got TWO injections of virus after arthritis onset, and on the right when mice got one injection after arthritis onset. What they are measuring is ankle width, paw width, and total disease score, measures of how much swelling was present.
Obviously the paw and ankle swelling did increase, the mice had just had onset of symptoms, the question is then how much the swelling increased.
And what you can see is that in both cases, the mice that got virus which increased levels of either p21 or p16 had major decreases in swelling, with narrower paws and ankles, and overall lower levels of disease. It looks like the two injections worked better than one. So increases in p21 and p16, which prevent cell cycling and thus decrease cell proliferation, worked to decrease swelling.
And it wasn't just the outward swelling that was decreased. The scientists also looked for markers of inflammation, such as IL-1beta, IL-6, and TNF-alpha, and all of these inflammatory markers were decreased when p16 or p21 was increased. So not only did it prevent massive cell proliferation in these mice, it also decreased inflammation.
This is some good news for people with rheumatoid arthritis, because it means that we may be able to use methods that increase p21 or p16 to decrease their symptoms and save them inflammation. To Sci it looks like p16 might be the better bet, because that one is very specific to the joints, while p21 is really everywhere. So p16 might be more likely to be made into a single injection, a series of injections, or a pill, while p21 might be more local.
Sci thinks this paper is really rather cool, but has only two issues:
1) They did measure paw width and inflammatory markers, but they didn't actually measure the level of pain the mice were in. It's easy to look at how sensitive the mice are to pain with a hot plate test (if you put a mouse's paw on a hot plate, it'll pull away. How long it takes to pull away is a measure of pain. If you give it painkillers, it will stay on longer), and it'd be nice to see these injections changing both the inflammation AND the pain of the mice.
2) Why don't we HAVE this yet?! This paper is old, it's a full 10 years old...and these treatments don't appear to have gone anywhere, even with local injections or something. This isn't Sci's field, but what's UP with that?
Well, hopefully we'll get something good out of it soon, and in the meantime, it's nice to know that there are still people out there looking for the answers.
Kimio Nasu, Hitoshi Kohsaka, Yoshinori Nonomura, Yoshio Terada, Hiroshi Ito, Katsuiku Hirokawa, and Nobuyuki Miyasaka (2000). Adenoviral Transfer of Cyclin-Dependent Kinase Inhibitor Genes Suppresses Collagen-Induced Arthritis in Mice Journal of Immunology, 165, 7246-7252

3 responses so far

  • CS Shelton says:

    I know a lot of people with arthritis who'd like an answer to that last question as well. Arthritis is some serious crap. Is it prohibitively expensive or risky to use viral cells in this way?

  • yellowfish says:

    That is really interesting for a couple of reasons- one really common RA drug, methotrexate, which is a fairly effective but awful medication that is often considered the gold standard, is also a chemotherapy agent (as well as being used for chemical abortions). So, it seriously impacts cell division (ask any hair-losing mouth-sore-having RA patient), and I never knew why it would work up until now. I assumed it just suppressed the immune system as a side effect of its 'real' effects, but it sounds like the cell division itself could be having an effect. Its also interesting because there are a number of (wildly expensive but incredibly effective) drugs that work on tnf-alpha, and I think now an IL-6 one, so the concept of a treatment upstream of both of those is pretty cool.
    I do wonder what happened to it, though and if its in the pipeline or not? these things go so painfully slowly...

  • michaela says:

    Sorry for the really late delay in replying- I was doing a google search on the old (though still hung on to) belief that RA is part of a personality disorder.

    Glad to have found this entry as it gave me a smile 🙂 Humour and facts and from a fellow scientist? Inconceivable!

    I know yellowfish won't get to read this but in case anyone else stumbles across this post: MTX works on all fast growing cells. So that includes the immune system but also skin and hair.

    I have lost a lot of hair with my RA medication, in fact right now I am thinking of shaving it all off as about 90% of it is less than two inches long. But my hair is too fine and to wavy to look good any length shorter than my shoulders. And my head is not a pretty shape 😉
    I have been on MTX, Arava, Enbrel, Plaquinel, SLZ and about to try Humira. I know I'll be looking at saying goodbye to that last 10% of long hair once I start injecting. Sigh.