Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?

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

“…Wei and colleagues point out that TNF-a is known to be a key driver of inflammatory arthritis. 1 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, 6 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.…”

“…Wei and colleagues postulate that the intra-articular use of soluble TNF-a Receptor II (sTNFRII) (etanercept, Enbrel 1 , 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. 1 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 role of progranulin in arthritis

“…Blocking IL‐1β protected against PTA development, whereas blocking TNF‐α signaling using the soluble extracellular domain of TNFR2 led to more severe OA, indicating that both IL‐1R and TNFR pathways are involved in the development of OA . This unexpected result suggests that another molecule (e.g., PGRN) might account for these interesting and paradoxical findings . Since PGRN has a much higher binding affinity (∼600 fold) for TNFR2 than TNF‐α and TNFR2 is thought to mediate immunosuppressive as well as anabolic effects, Enbrel® may competitively bind to PGRN, resulting in abolished effect of the PGRN/TNFR2‐mediated protective/anabolic pathway …”

“…143,144 This unexpected result suggests that another molecule (e.g., PGRN) might account for these interesting and paradoxical findings. 145 Since PGRN has a much higher binding affinity (ß600 fold) for TNFR2 than TNF-␣ and TNFR2 is thought to mediate immunosuppressive as well as anabolic effects, Enbrel R may competitively bind to PGRN, resulting in abolished effect of the PGRN/TNFR2-mediated protective/anabolic pathway. 145,146 Conclusions PGRN has potent anti-inflammatory properties and directly binds TNFRs, including TNFR1, TNFR2, and DR3.…”

“…145 Since PGRN has a much higher binding affinity (ß600 fold) for TNFR2 than TNF-␣ and TNFR2 is thought to mediate immunosuppressive as well as anabolic effects, Enbrel R may competitively bind to PGRN, resulting in abolished effect of the PGRN/TNFR2-mediated protective/anabolic pathway. 145,146 Conclusions PGRN has potent anti-inflammatory properties and directly binds TNFRs, including TNFR1, TNFR2, and DR3. The PGRN-TNFR interaction has been independently confirmed and extended in various cell types and conditions (Table 1).…”