Title: A novel therapeutic target for arthritis pain
Background: Arthritis-associated chronic pain is a major concern for all patients and is often exacerbated due to comorbidities (for example, obesity). We have reported a novel granulocyte macrophage-colony stimulating factor (GM-CSF)/CCL17 axis in monocytes/macrophages. Given that there are reported encouraging clinical data on anti-GM-CSF monoclonal antibody (mAb) therapy in rheumatoid arthritis and osteoarthritis (OA) pain and disease, we therefore proposed that the chemokine, CCL17, could be a novel therapeutic target in different types of arthritis by examining its relevance in mouse models of (i) inflammatory arthritis, (ii) OA and (iii) obesity-exacerbated OA.
Methods: To study the relevance of CCL17 in arthritis, we used the following mouse models: (i) for inflammatory arthritis, zymosan-induced arthritis and antigen-induced arthritis models; (ii) for OA, the destabilization of medial meniscus (DMM)-induced OA, monosodium iodoacetate (MIA)-induced OA and collagenase-induced OA (CiOA) models; (iii) for obesity-exacerbated OA, an eight-week 60% high-fat diet protocol was used prior to the induction of an OA model. These models were either induced in CCL17 gene-deficient (Ccl17E/E) mice with wild-type (WT) mice as a control group or in WT mice treated with an anti-CCL17 mAb therapeutic protocol (i.e. following the onset of pain). We assessed the development of pain-like behaviour and joint pathology using the static weight bearing method and histological analysis, respectively.
Results: For inflammatory arthritis, in comparison to WT mice, Ccl17E/E mice were protected from developing pain-like behaviour and joint pathology, while, interestingly, the degree of joint inflammation was similar to that seen in WT mice. Therapeutic blockade of CCL17 showed efficacy in ameliorating pain-like behaviour and joint pathology. For both OA and obesity-exacerbated OA, similar to inflammatory arthritis, we again found a similar dependence on CCL17 for pain-like behaviour and joint pathology using Ccl17E/E mice. We also consistently found therapeutic efficacy of anti-CCL17 mAb therapy in the OA models.
Conclusions: In contrast to the well-recognized chemotactic role of CCL17 (e.g. preferential Th2 cell chemotaxis), these data reveal a novel, non-chemotactic and algesic role of CCL17 in arthritis-associated pain and disease, and suggest that it could be a therapeutic target in different types of arthritis.
Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria 3050 Australia