Forgive my excitement, but I love a good OA signaling mechanism as much as the next person. And since there are only 2 (TWO!) days with OA sessions at the entire EULAR meeting, today is an OA double-header for me.
It isn't news anymore that many forms of OA have at least a chronic, low-grade inflammatory component, which includes the production of chemokines from chondrocytes (among other inflammatory molecules). A debate has been lingering for the past few years about the role of a specific chemokine called CCL2, also known as MCP-1 (monocyte chemoattractant protein 1) in OA. We know from multiple animal models of OA that CCL2 is increased transiently after joint injury, and that CCL2 is increased in human OA chondrocytes. Controversy has circled around whether it is relevant to disease progression, since studies have been mixed with some showing protection against experimental post-traumatic OA (PTOA) with pharmacologic inhibitors of the CCL2 receptor CCR2, while genetic studies largely haven't shown protection against joint damage.
More evidence was presented today that it may in fact be an important player, with two caveats.
Following up on two compelling new studies underscoring a role played by IL-6 in driving knee PTOA and knee calcification that were published in Annals of Rheumatic Disease in late 2016, Augustin Latourte (Paris, France) showed that CCL2 is transiently increased in a post-traumatic OA model in mice. This of course is already known, but what is new is that they have now uncovered a potential link between CCR2 and IL-6 signaling. In the Basic and Translational Science Session, this group showed that IL-6 induces CCL2 and another CCR2 ligand, CCL7 in chondrocytes, along with cartilage damaging proteases like MMP-3 and MMP-13. As we know from extensive immunology literature, much of IL-6 signalling is mediated via Stat3-mediated mechanisms. According to Latourte and colleagues, blocking the chemokine receptor CCR2 in chondrocytes reduced the protease-inducing effects of IL-6 and cartilage damage in cartilage explants.
Obviously, this is only in vitro data and the mechanism is being defined in animal tissues, which are important limitations. Notwithstanding, a nice story is shaping up that implicates IL-6 signaling in driving cartilage damage in OA. When coupled with the recent in vivo studies demonstrating the protective effect of blocking IL-6 or Stat3 signaling in mouse models of post-traumatic OA, the identification of CCR2 signaling (which we already know is a feature of joint injury-related OA) is a significant step forward. With good pharmacologic inhibitors already available that work at various nodes in this proposed mechanism, further work needs to be done before we can pass the CCR2 or IL-6 inhibitors to the left (or right) knee for PTOA.
Dr. Appleton completed the combined MD/PhD program at Western University in Canada and is now a rheumatologist and clinician scientist at St. Joseph’s Hospital in London, Canada. In addition to his rheumatology practice, Dr. Appleton oversees a translational biology research program in early osteoarthritis.View Full Bio