Secondary arthritis: How does it start?

I've been posting a lot lately about all my athletic endeavors, and realized that I have been not incorporating updates about my academic life. Truth be told, the last month has left me feeling as if my research was just kind of hanging out on the back burner and my athleticism was taking over.

Luckily, I'm back in the lab, doing histology, acquiring samples, and even attempting to engineer some new drug delivery methods. Even though my research is in the field of engineering, it's definitely driven by biology and fundamental molecular pathways of inflammation. I won't get too far into that. What I will get into is the impact that my research will (hopefully) have on the general public. What am I referring to? Osteoarthritis, of course.

Recently, a fellow blogger friend of mine, a principle scientist at the University of Washington, posted this treat on his blog. I felt like he posted it just for me! Now, maybe he did, maybe he didn't, but holy cripes, was I excited. It just piles on the motivation for me to get my publications wrapped up and shipped out! And then I was slightly disappointed (why wasn't my collabo's work featured in NYTs!? Are our university marketing departments slacking?!), but I'm still excited.

The NYT's article is referring to a manuscript by Dr Chu's group that was just published in the American Journal of Sports Medicine in December of this year. In the study, the authors look at chondrocyte death in cartilage after blunt impaction to the bovine articular cartilage explants. The translational research from in vitro cow studies to real-life human injuries still needs to be made, by my collaborators and I have published several papers related to impaction-induced arthritis in a closed-joint traumatic model in the last year and a half [1,2,3]. We've even identified potential treatments! That's exciting news.

So what's the story? Basically, impaction-induced arthritis is fairly common, and can develop after a car accident (where the knee hits the dashboard) or a sports injury. Although the incident of injury is a specific time point that can be linked to joint degradation, the exact mechanism by which arthritis accelerates is what stimulates curiosity. You see, secondary osteoarthritis (OA) develops much faster than primary (age related) OA. Along with trauma, it can also be caused by obesity, genetic disorders, or joint malalignment. Instead of taking a lifetime to develop, it can be seen radiologically (ie. x-ray) within the first few years, especially following traumatic injury such as anterior cruciate ligament (ACL) rupture. In fact, histological changes to the cartilage* have been found within a year following injury [4]. How does trauma accelerate cartilage degradation so much? What factors are involved, and how can we slow it down and prevent it? There are so many factors that are not well understood. Take for example ACL repair. If a soccer player tears their ACL, they will probably have it fixed because it is well understood that abnormal loading in the knee will lead to arthritic changes to the cartilage. Why, then, ten years later, does that soccer player still get OA? The answers are not yet known.

*Before I get too far in, though, I should probably explain the anatomy of the knee a bit. The long bones of the leg are covered at the ends with something called cartilage (I'm sure most of you have heard of this, yeah?). The picture to the right is a pig's knee, the tibial plateau to be exact. Imagine looking at your shank from the top-down. That's what it would look like if your femur and ligaments (ACL, pcl, mcl, lcl) were no longer intact and your shank was removed from your body (and my hands, with the blue gloves, were holding it). Cartilage, outlined in the red hash line to the right, actually covers the entire tibial plateau, even under those yellow-outlined rubbery looking tissues (which are the menisci).  The meniscus attaches to the tibial plateau and is super important, because it helps protect the cartilage underneath, and distributes loads during walking, running and jumping. It's like a shock absorber for the knee.

Another key player in knee joint health is the ACL (the nub of which is outlined in blue). The ACL prevents the tibia from moving forward during walking, running and jumping. If it gets torn, then the knee joint stability goes all out of wack. Patients with torn ACLs can end up with meniscal tears, accelerated cartilage damage, and OA. That's why so many people have their ACLs repaired.

In impaction-induced ACL rupture, the cartilage receives a single, high-energy impact during compression. The cartilage isn't used to this type of behavior, because it typically doesn't see such high energy levels, thanks in part to the meniscus (and avoidance of these types of injuries). But when the cartilage does see the high, fast compression, it doesn't really know what to do. Because the cartilage is made up of a bunch of cells called chondrocytes (surrounded by matrix called collagen), the cells may go into something called apoptosis, or programmed cell death, or necrosis (premature death, or suicide). In necrosis, cells release a bunch of signals that say "HELP! DANGER" and then they die, and obviously can no longer perform their roles as chondrocytes. [There's another word, called chondroptosis, but that may be too far for this blog.] Anyway, necrotic triggers can be inflammatory markers, which can trigger a whole plethora of events, or macrophage recruiters, which eat up stuff (like dead cells!). In apoptosis, the cells just casually die, no signals, they just kinda fade into black, like a Metallica song.

So what does this mean? In impaction induced arthritis, it may mean that - regardless of whether or not the ACL rupture is fixed - the joint may be predisposed to OA no matter what. The cells initial signaling (if they are indeed going through necrosis) may open the whole can of worms. Not good news at all.  What can we do about it? We need to understand the whole system more. Maybe impaction isn't the end-all and be-all that is traumatic OA. If I am out riding my snowmobile and bash my knee, I don't want to be cursed with the impending OA [unfortunately, this story is something that happened to my boyfriend in 2008].

We need to understand the system better. We don't know yet how chondrocytes really die after traumatic impaction, and we don't know if they will be replaced by healthy, viable cells. So many questions are still out there. Does it really matter if the cells of the cartilage die? What's the "threshold" for cartilage impaction magnitudes, before which chondrocytes stay alive? Are other tissues influenced by chondrocyte cell death, or the event of impaction for that matter?

We're getting there, and researchers at Michigan State University have recently shown that certain molecules, called surfactants, can actually protect the chondrocytes before they are impacted and may even "cushion" them for the impending impact [1]. It's almost like the surfactant wraps the cells in plastic bubble wrap. But is this a suitable treatment? What implications does it have on the rest of the joint (or does it go systemic and cause problems elsewhere?). Although cartilage is the main indicator for OA development and progression, my doctoral research is focusing on other soft tissues of the knee, namely the meniscus, to see how impaction influences the viability and health of the other major players of knee joint health.

When it comes down to the nitty-gritty, we really don't know why some people get secondary OA after traumatic impaction and some don't. Right now, there are just so many confounding variables. And its important to remember that correlation does not necessarily mean causation. Will my boyfriend get OA by the time he's 35 because he did an Ironman a year out from tearing his PCL after hitting a tree? I don't know. I hope not, but it's possible. It's possible that the injury did him in, or that the surgery itself to fix the PCL did more damage. Or, the opposite is true; maybe he's better off because he started training for Ironman, because he ramped up his cycling training (cyclic shear-type loading on his knee), strengthened his quads, and worked on his stabilizing muscles. In truth, he's stronger now than before he was injured. Anecdotal? Of course. Interesting? You bet.

That's all I got for now!

--I should clarify that the work discussed in the NYT's article was all in vitro work. The researchers took explants (biopsy punches) from cow knees (the cows were already dead, don't worry) and then impacted them with a weight from different heights (which translated into different impaction energies). The impaction was directly applied to the surface of the explant. In the research I'm involved with (cited in this post), our impactions were applied to the closed-joint of the rabbit knee either immediately after the rabbit was killed or while it was anesthetized.. Other structures were influenced by impaction (muscle, bone, meniscus). It's important to know the difference, because in Chu's study, the impaction energy was much lower (1.07J) than the impaction energy we used (13J).

References

1. Isaac DI, Golenberg N, Haut RC. Acute repair of chondrocytes in the rabbit tibiofemoral joint following blunt impact using P188 surfactant and a preliminary investigation of its long-term efficacy. J Orth Res, 2009 Oct 29. [Epub ahead of print]

2. Killian ML, Isaac DI, Haut RC, Dejardin LM, Leetun D, Haut Donahue TL.Traumatic Anterior Cruciate Ligament Tear and its Implications on Meniscal Degradation: A Preliminary Novel Lapine Osteoarthritis Model. J Surg Res, 2009 Apr 5. [Epub ahead of print]

3. Isaac DI, Meyer EG, Haut RC. Chondrocyte damage and contact pressures following impact on the rabbit tibiofemoral joint. J Biomech Eng, 2008 Aug;130(4):041018.

4. Nelson F, Billinghurst RC, Pidoux I, Reiner A, Langworthy M, McDermott M, Malogne T, Sitler DF, Kilambi NR, Lenczner E, Poole AR. Early post-traumatic osteoarthritis-like changes in human articular cartilage following rupture of the anterior cruciate ligament. OA &C. 2006 Feb;14(2):114-9. Epub 2005 Oct 20.