Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis

Abstract

Objective We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA). Method We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter. Results Testing early vs. delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1–4wks post-surgery or moderate, 4–8wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped. Conclusions Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.

Can we target CCR2 to treat osteoarthritis? The trick is in the timing!

“…In the current issue of Osteoarthritis and Cartilage , Longobardi and colleagues report the first studies with prolonged therapeutic administration of a CCR2-RA (RS-504393) in the murine DMM model [10]. They found that sustained pharmacological blockade of CCR2 mimics the findings in Ccr2 null mice.…”

“…It should also be considered that CCR2 is a widely expressed molecule, present on monocytes, T cells, neurons, osteoclasts, and chondrocytes [4, 10]. In cartilage, a number of chemokines, including the three CCR2 ligands, are upregulated in rodent models of OA, but the role of chemokine signaling within cartilage in OA pathogenesis remains unclear [4, 10].…”

“…In cartilage, a number of chemokines, including the three CCR2 ligands, are upregulated in rodent models of OA, but the role of chemokine signaling within cartilage in OA pathogenesis remains unclear [4, 10]. Therefore, the complex interplay between tissues and cells in the joint, and temporal changes in these interactions, may contribute to the observed phenotype in mice where CCR2 is blocked genetically or pharmacologically.…”

Time to be positive about negative data?

“…Timing of genetic deletion or treatment may be critical for disease outcome. In this issue, we report the failure to show a significant reduction in cartilage degradation in Ccl2 and Ccr2 constitutive knockout mice [15], yet targeting the pathway after the initial injury appears to be effective at inhibiting disease [16]. In other words, molecules may have different roles at different times of disease.…”

Models to define the stages of articular cartilage degradation in osteoarthritis development

“…A recent review on standardizing OA definition highlights the need to stage disease, separating OA development, OA progression and early detection (Kraus et al 2015). In addition, it was recently found different outcomes between short-and longterm inhibition of CCR2, suggesting this chemokine may play different roles during OA progression (Longobardi et al 2016). For example, is the beneficial effect of a specific treatment due to a protection against initiation of AC lesions, or because of interference with a specific event involved in progression of joint degeneration?…”