CCL2 and CCR2 regulate pain-related behaviour and early gene expression in post-traumatic murine osteoarthritis but contribute little to chondropathy

Abstract

SummaryObjectiveThe role of inflammation in structural and symptomatic osteoarthritis (OA) remains unclear. One key mediator of inflammation is the chemokine CCL2, primarily responsible for attracting monocytes to sites of injury. We investigated the role of CCL2 and its receptor CCR2 in experimental OA.DesignOA was induced in 10 weeks old male wild type (WT), Ccl2−/− and Ccr2−/− mice, by destabilisation of the medial meniscus (DMM). RNA was extracted from whole joints at 6 h and 7 days post-surgery and examined by reverse transcription polymerase chain reaction (RT-PCR). Gene expression changes between naïve and DMM-operated mice were compared. Chondropathy scores, from mice at 8, 12, 16 and 20 weeks post DMM were calculated using modified Osteoarthritis Research Society International (OARSI) grading systems. Changes in hind paw weight distribution, as a measure of pain, were assessed by Linton incapacitance.ResultsAbsence of CCL2 strongly suppressed (>90%) selective inflammatory response genes in the joint 6 h post DMM, including arginase 1, prostaglandin synthase 2, nitric oxide synthase 2 and inhibin A. IL6, MMP3 and tissue inhibitor of metalloproteinase 1 were also significantly suppressed. Similar trends were also observed in the absence of CCR2. A lower average chondropathy score was observed in both Ccl2−/− and Ccr2−/− mice at 12, 16 and 20 weeks post DMM compared with WT mice, but this was only statistically significant at 20 weeks in Ccr2−/− mice. Pain-related behaviour in Ccl2−/− and Ccr2−/− mice post DMM was delayed in onset.ConclusionThe CCL2/CCR2 axis plays an important role in the development of pain in murine OA, but contributes little to cartilage damage.

A mouse model for chronic pain-induced increase in ethanol consumption

“…The present study was designed to determine if using a combination of a well-established model of chronic pain and alcohol preference/consumption in mice – surgical destabilization of the medial meniscus (DMM) [7; 9; 14; 16] and the two-bottle ethanol choice [2], respectively – is appropriate for studying chronic pain-induced ethanol intake. A positive outcome would allow further investigation of this approach as an appropriate avenue to investigate the basis of the co-morbidity of pain and alcohol intake that results in alcohol abuse clinically.…”

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

“…When a small number of Ccr2 null mice were first tested in a surgical model of OA induced by destabilization of the medial meniscus (DMM), these mutant mice developed similar cartilage damage as wild-types over an 8-week period [7]. In the largest study yet, two independent laboratories recently confirmed an absence of protection from cartilage damage in Ccr2 null mice 8 weeks after DMM, while there was a slight trend toward chondroprotection at 12,16, and 20 weeks [8]. In contrast, a recent study reported partial protection from cartilage damage and synovitis, 20 weeks after DMM [9]; notably, this study was conducted in 20-week old mice, which resulted in more severe joint damage in wild-type mice by week 20 compared to surgery in 10-week old mice [8, 9].…”

“…In the largest study yet, two independent laboratories recently confirmed an absence of protection from cartilage damage in Ccr2 null mice 8 weeks after DMM, while there was a slight trend toward chondroprotection at 12,16, and 20 weeks [8]. In contrast, a recent study reported partial protection from cartilage damage and synovitis, 20 weeks after DMM [9]; notably, this study was conducted in 20-week old mice, which resulted in more severe joint damage in wild-type mice by week 20 compared to surgery in 10-week old mice [8, 9]. While the protective effect was statistically significant, Ccr2 null mice still developed significant joint damage in this study [9].…”

“…Thus, it could be hypothesized that CCR2 signaling may be crucial for recruiting cells that are involved in resolving acute post-injury inflammation and/or promoting repair, which may partly explain the absent or modest joint protective effects of Ccr2 ablation or sustained pharmacological CCR2 blockade, as well as the dependency of the effect size on the severity of the model. In this respect, Miotla Zarebska et al found distinctly altered inflammatory responses in whole-joint extracts from Ccr2 null mice compared to wild-types, 6 hours and 7 days after destabilization [8]. Notably, in wild-type mice, one of the most strongly induced genes – besides the CCR2 ligand, Ccl2 – was Arg1 , the gene encoding arginase 1, which is expressed in macrophages and partly defines the M2 macrophage phenotype [14].…”

Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice

“…Chemokines also play an important role in the pathology of RP [6]. In particular, chemokine (C-C motif) ligand 2 (CCL2) directs microglia to the site of injury or infection [7, 8]. Vascular cell adhesion molecule 1 (VCAM-1), an adhesion molecule, also plays a role in chemotaxis [9, 10].…”