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. 2017 Mar;25(3):406-412.
doi: 10.1016/j.joca.2016.10.008. Epub 2016 Oct 13.

CCL2 and CCR2 Regulate Pain-Related Behaviour and Early Gene Expression in Post-Traumatic Murine Osteoarthritis but Contribute Little to Chondropathy

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Free PMC article

CCL2 and CCR2 Regulate Pain-Related Behaviour and Early Gene Expression in Post-Traumatic Murine Osteoarthritis but Contribute Little to Chondropathy

J Miotla Zarebska et al. Osteoarthritis Cartilage. .
Free PMC article

Abstract

Objective: The 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.

Design: OA 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.

Results: Absence 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.

Conclusion: The CCL2/CCR2 axis plays an important role in the development of pain in murine OA, but contributes little to cartilage damage.

Keywords: Animal model; CCL2; CCR2; Osteoarthritis; Pain.

Figures

Fig. 1
Fig. 1
Chondropathy scores are not substantially different in WT, Ccl2−/−and Ccr2−/−mice. 10 weeks old, male WT (C57Bl/6J), Ccl2−/− and Ccr2−/− mice underwent DMM. Joints were harvested at 8, 12, 16 and 20 weeks post DMM for histological analysis and scored according to modified OARSI grading systems (each group using subtly different scores). Chondropathy scores (Vincent group) were pooled from several experiments performed over 4 years (A). Pink – experimental data acquired pre-2013; grey – experimental data acquired post-2013. Representative histology is shown (B). Histological scores using the same Ccr2−/− strain but performed in a different laboratory (Malfait) are shown (C). Data was analysed by analysis of variance (ANOVA) with Bonferroni post hoc testing, *P ≤ 0.05. All other results non-significant.
Fig. 2
Fig. 2
Onset of pain-related behaviour is delayed in Ccl2−/−and Ccr2−/−mice post DMM. 10 weeks old, male WT (C57Bl/6J), Ccl2−/− and Ccr2−/− mice underwent DMM or sham surgery. Pain-related behaviour was assessed twice weekly for the first week, then weekly by Linton Incapacitance testing. Statistical significance (ANOVA) was determined by comparing the difference between destabilised and sham-operated responses for Ccl2−/− and Ccr2−/− mice. Pain-related behaviour in WT mice is shown along side.

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