Reply to “Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?” by Wei et al.

Dear Editors, We thank the authors for their kind comments regarding our work exploring the relationship of proinflammatory cytokines in the post-injury response and the development of post-traumatic arthritis (PTA) after articular fracture. Wei and colleagues postulate that the intra-articular use of soluble TNF-a Receptor II (sTNFRII) (etanercept, Enbrel, Amgen, Thousand Oaks, CA) may paradoxically exacerbate the development of PTA by inhibiting PGRN/TNFR2, a protective/anabolic pathway activated when progranulin (PGRN) binds to TNFa Receptor 2. The authors present work that supports PGRN as an inhibitor of THR-a mediated inflammation. While this is an interesting hypothesis, it is not clear at this point whether the data from our work supports this. The authors cite our manuscript summarizing the collective body of work (Olson et al). However the details can be found in several more specific manuscripts. Lewis et al provided a detailed analysis of the post-injury pro-inflammatory cytokine profile while exploring the difference between C57BL/6 mice that develop PTA and MRL/MpJ mice that are protected against PTA after closed articular fracture. In this work, synovial gene expression demonstrated that within 4h of injury there was a significant (over 700-fold) increase in IL-1b as compared with the more modest 12-fold increase in TNF-a expression. An increase in synovial levels of TNF-a were not detectably different at any time point in the first 7 days after injury, whereas there was a significant increase in IL-1b levels at 4 and 24h after injury. Furman and Mangiapani et al compared prolonged systemic vs a single intra-articular injection with either saline, sTNFRII, or IL-1 Receptor antagonist (IL-1Ra) (anakinra, Kineret, Biovitrum, Stockholm, Sweden). Notable in this work is the observation that the highest Mankin score occurred in the systemic IL-1Ra treatment group. There was no difference in Mankin scores between the saline and sTNFRII groups for either intra-articular or systemic administration. This suggests that inhibition of the PGRN/TNFR2 protective/anabolic pathway did not result in a paradoxical exacerbation of PTA development. Kimmerling et al. found similar results when using elastin-like polypeptide as a drug depot to provide a sustained drug delivery of intra-articluar injected agents. In this paper, both the use of sTNFRII alone, or in combination with IL1-Ra, resulted in higher Mankin scores in the experimental (fractured) knee as compared to the control knee. Wei and colleagues point out that TNF-a is known to be a key driver of inflammatory arthritis. Further, they point out that in contrast to our results with intra-articular injection with Etanercept, two references are cited where use of TNF-a inhibitors reduced the severity of PTA. Specifically the authors cited the intra-articular injection with Infliximab (Remicade, a mouse-human IgG1 chimeric anti-TNF monoclonal antibody) beginning 8 weeks after an ACL transection in rabbits, and systemic injection of adalimumab (Humira, a human monoclonal antibody of TNF-a) for 12 weeks in an ACL transection model in rats with injections beginning at time of ACL transection. These reports point to a possible role of TNF-a in the later stages of the post-injury response to fracture and a possible reparative role of the PGRN/TNFR2 pathway after injury. However, it is also important to note that the ACL transection model differs significantly from the intra-articular fracture model used in the majority of our studies. Specifically, our model involves a severe fracture of the bone and articular cartilage in the joint, and factors associated with more rapid bone healing appear to decrease the severity of PTA in this model. In addition in our investigation prolonged systemic administration of Etanercept resulted in severe PTA. Given the potential role of TNF-a in bone repair, and the importance of bone healing after an articular fracture, inhibition of TNF may delay repair of the articular fracture and thus exacerbate PTA. It is also possible that IL-1 plays a dominant role in the acute events involved in the development of PTA after an acute articular injury. As the acute postinjury response of articular injury in humans is poorly understood, we agree that much work is needed in this area to help improve our understanding of PTA, and we thank Dr. Wei and colleagues for their commentary on our work.