CCL17 blockade as a therapy for osteoarthritis pain and disease

Abstract

BackgroundGranulocyte macrophage-colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of a number of inflammatory diseases and in osteoarthritis (OA). We identified previously a new GM-CSF→Jmjd3→interferon regulatory factor 4 (IRF4)→chemokine (c-c motif) ligand 17 (CCL17) pathway, which is important for the development of inflammatory arthritis pain and disease. Tumour necrosis factor (TNF) can also be linked with this pathway. Here we investigated the involvement of the pathway in OA pain and disease development using the GM-CSF-dependent collagenase-induced OA (CiOA) model.MethodsCiOA was induced in C57BL/6 wild-type (WT), Irf4−/−, Ccl17E/E, Ccr4−/−, Tnf−/− and GM-CSF−/− mice. Additionally, therapeutic targeting of CCL17, Jmjd3 and cyclooxygenase 2 (COX-2) was evaluated. Development of pain (assessment of weight distribution) and OA disease (histologic scoring of synovitis, cartilage destruction and osteophyte size) were assessed. Synovial joint cells, including neutrophils, macrophages, fibroblasts and endothelial cells, were isolated (cell sorting) and gene expression analyzed (quantitative PCR).ResultsStudies in the gene-deficient mice indicated that IRF4, CCL17 and the CCL17 receptor, CCR4, but not TNF, were required for CiOA pain and optimal cartilage destruction and osteophyte size. Therapeutic neutralization of CCL17 and Jmjd3 ameliorated both pain and disease, whereas the COX-2 inhibitor only ameliorated pain. In the synovium Ccl17 mRNA was expressed only in the macrophages in a GM-CSF-dependent and IRF4-dependent manner.ConclusionsThe GM-CSF→Jmjd3→IRF4→CCL17 pathway is important for the development of CiOA, with CCL17 thus being a potential therapeutic target for the treatment of both OA pain and disease.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1560-9) contains supplementary material, which is available to authorized users.

Adipose Tissue is a Critical Regulator of Osteoarthritis

“…This implicates a role for the IL-1 and IL-6/IL-12 family of cytokines in protection and susceptibility to OA, which has been postulated as key therapeutic target networks for OA (26). In addition, we observed decreased levels for TARC/CCL-17 in LD DMM limbs, which is of interest as CCL-17 blockade has been demonstrated as a therapeutic candidate for OA structure and pain (38). In the fat rescue groups, we observed increased circulating levels of TARC/CCL-17, but decreased SF levels for TARC/CCL-17.…”

GM-CSF in inflammation

“…CCL17 may not necessarily be acting as a T cell chemokine in its control of inflammation and its associated pain; i.e., it appears that CCL17 has other, hitherto undefined, functions (Weber et al, 2011;Heiseke et al, 2012;Cook et al, 2018b;Lee et al, 2018). In this connection CCL17-driven inflammatory pain is cyclooxygenase 2 dependent, suggesting eicosanoid involvement ( Fig.…”

“…There are conflicting data as to whether the CCL17 receptor, CCR4, is expressed in neurons (Oh et al, 2001;Thakur et al, 2014;Li et al, 2016;Cook et al, 2018a); such expression would indicate the possibility of their direct activation by CCL17. Human microglial cells have been reported to express CCR4 (Etemad et al, 2012), suggesting that CCL17 could act at this level in pain development; however, blockade of arthritic pain by systemic anti-CCL17 mAb administration suggests a peripheral algesic action of CCL17, at least in the models studied (Achuthan et al, 2016;Cook et al, 2018a;Lee et al, 2018). Intriguingly, as regards the role of CCL17 in inflammation, CCL17 depletion can result in regulatory T cell expansion in atherosclerosis and colitis models, leading to disease reduction (Weber et al, 2011;Heiseke et al, 2012).…”

Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

“…Persistent inflammation with fibrosis in the synovial tissue of MIA model was accompanied by pain avoidance behavior before articular cartilage degeneration and by an increase in calcitonin gene-related peptide (CGRP)-positive fibers in the DRG and synovium [103]. CIOA induced an increase in interferon regulatory factor 4 (IRF-4), CCL-17 and chemokine (c-c motif) receptor 4 (CCR-4), the CCL-17 receptor; gene-deficient mice were protected from pain as well as joint destruction, indicating that these molecules are required for the development of OA pain [104]. The therapeutic neutralization of CCL-17 ameliorated both pain and joint damage, whereas the cyclooxygenase 2 (COX-2) inhibitor only ameliorated pain [104].…”

“…CIOA induced an increase in interferon regulatory factor 4 (IRF-4), CCL-17 and chemokine (c-c motif) receptor 4 (CCR-4), the CCL-17 receptor; gene-deficient mice were protected from pain as well as joint destruction, indicating that these molecules are required for the development of OA pain [104]. The therapeutic neutralization of CCL-17 ameliorated both pain and joint damage, whereas the cyclooxygenase 2 (COX-2) inhibitor only ameliorated pain [104].…”