Disease Progression and Phasic Changes in Gene Expression in a Mouse Model of Osteoarthritis

Loeser, Richard F.; Olex, Amy L.; McNulty, Margaret A.; Carlson, Cathy S.; Callahan, Michael F.; Ferguson, Cristin M.; Fetrow, Jacquelyn S.

doi:10.1371/journal.pone.0054633

Cited by 113 publications

(144 citation statements)

References 30 publications

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“…Further, microarray analyses of genes expressed in knees of mice with surgery-induced OA showed that Ccl2 is upregulated as early as 6 hours and 7 days after surgery when there is no apparent histological changes) relative to sham-operated controls (see online supplementary figure S1A). 18 20 To evaluate whether increased Ccl2 gene expression was sustained through the progression of OA, we analysed synovial Ccl2 expression at 12 weeks after DMM, when significant cartilage degradation is apparent 18 19 21. We found that synovial Ccl2 mRNA was significantly upregulated in DMM-operated compared with sham-operated mice (see online supplementary figure S1B).…”

Section: Resultsmentioning

confidence: 99%

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis

et al. 2016

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Objectives While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/ CCR5 chemokine axes in OA pathogenesis. Methods Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains. Results Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA. Conclusions Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.

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Section: Resultsmentioning

confidence: 99%

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis

et al. 2016

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“…Secondly, we investigated whether ADAMTS-5 blockade altered mechanical allodynia and associated production of the pro-algesic chemokine, monocyte chemoattractant protein (MCP)-1, by dorsal root ganglia (DRG) neurons [9]. We chose to start treatment 4 weeks after DMM surgery since, by this time, mild structural damage is evident [14-16] and mechanical allodynia has fully developed [8, 9], reflecting an early stage of disease.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis

Miller

Tran

Ishihara

et al. 2016

Osteoarthritis and Cartilage

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Objective The primary goal of this study was to test the disease-modifying effect of blocking a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 with a neutralizing monoclonal antibody (mAb) starting 4 weeks after destabilization of the medial meniscus (DMM) in the mouse. We also investigated whether ADAMTS-5 blockade reversed mechanical allodynia and decreased monocyte chemoattractant protein (MCP)-1 production by dorsal root ganglia (DRG) cells. Methods Ten-week old male C57BL/6 mice underwent DMM surgery and were either left untreated or treated with anti-ADAMTS-5 mAb or IgG2c isotype control mAb starting 4 weeks after surgery. Knees were collected for histopathology 4 or 12 weeks later. Mechanical allodynia was monitored biweekly in the ipsilateral hind paw through 16 weeks. DRG were collected and cultured 8 weeks after DMM for analysis of MCP-1 production. Results By 4 weeks after DMM, mild cartilage degeneration was evident in the medial compartment, small osteophytes were present, and subchondral bone sclerosis was established. By 16 weeks after surgery, significant cartilage deterioration was apparent on the medial tibial plateaux and medial femoral condyles, osteophyte size had increased, and subchondral bone sclerosis was maintained. Treatment with ADAMTS-5 mAb from week 4-16 after surgery slowed cartilage degeneration and osteophyte growth but did not affect subchondral bone sclerosis. Moreover, ADAMTS-5 blockade resulted in temporary reversal of mechanical allodynia, which correlated with decreased MCP-1 production by cultured DRG cells. Conclusions This study suggests therapeutic efficacy of an ADAMTS-5 mAb in the DMM model, when therapy starts early in disease.

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“…We recently generated a microarray dataset that assessed gene expression changes over time during the early stages of OA in a commonly used mouse model 8 . In this model, OA develops after surgical destabilization of the medial meniscus (DMM model).…”

Section: Introductionmentioning

confidence: 99%

“…In order to be able to take a more systems level approach, we examined gene expression changes in the joint as an organ by extracting RNA from a pool of tissues including cartilage, subchondral bone, meniscus and the joint capsule with synovium. Using this dataset, we previously filtered a total of 371 genes into 27 clusters with various temporal gene expression patterns 8 . These clusters included many genes previously associated with OA—such as COMP, MMP14, TIMP2, SDC1, DDR2, TGFB2, MMP13, FMOD, BGN, LECT1, S100B and multiple collagen genes—and elucidated their expression kinetics during the onset of OA.…”

Section: Introductionmentioning

confidence: 99%

Integration of gene expression data with network-based analysis to identify signaling and metabolic pathways regulated during the development of osteoarthritis

Olex

Turkett

Fetrow

et al. 2014

Gene

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Osteoarthritis (OA) is characterized by remodeling and degradation of joint tissues. Microarray studies have led to a better understanding of the molecular changes that occur in tissues affected by conditions such as OA; however, such analyses are limited to the identification of a list of genes with altered transcript expression, usually at a single time point during disease progression. While these lists have identified many novel genes that are altered during the disease process, they are unable to identify perturbed relationships between genes and gene products. In this work, we have integrated a time course gene expression data set with network analysis to gain a better systems level understanding of the early events that occur during the development of OA in a mouse model. The subnetworks that were enriched at one or more of the time points examined (2, 4, 8, and 16 weeks after induction of OA) contained genes from several pathways proposed to be important to the OA process, including the extracellular matrix-receptor interaction and the focal adhesion pathways and the Wnt, Hedgehog and TGF-β signaling pathways. The genes within the subnetworks were most active at the 2 and 4 week time points and included genes not previously studied in the OA process. A unique pathway, riboflavin metabolism, was active at the 4 week time point. These results suggest that the incorporation of network-type analyses along with time series microarray data will lead to advancements in our understanding of complex diseases such as OA at a systems level, and may provide novel insights into the pathways and processes involved in disease pathogenesis.

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Disease Progression and Phasic Changes in Gene Expression in a Mouse Model of Osteoarthritis

Cited by 113 publications

References 30 publications

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis

CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis

Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis

Integration of gene expression data with network-based analysis to identify signaling and metabolic pathways regulated during the development of osteoarthritis

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