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. 2016 Feb;24(2):299-306.
doi: 10.1016/j.joca.2015.09.005. Epub 2015 Sep 26.

Therapeutic Effects of an anti-ADAMTS-5 Antibody on Joint Damage and Mechanical Allodynia in a Murine Model of Osteoarthritis

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Free PMC article

Therapeutic Effects of an anti-ADAMTS-5 Antibody on Joint Damage and Mechanical Allodynia in a Murine Model of Osteoarthritis

R E Miller et al. Osteoarthritis Cartilage. .
Free PMC article

Abstract

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 to 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.

Keywords: ADAMTS-5; Mouse model; Osteoarthritis; Pain.

Conflict of interest statement

Conflict of interest: JL is a current employee of, and shareholder in, GlaxoSmithKline which holds patent application WO2011002968A2.

Figures

Figure 1
Figure 1
Experimental design. Treatment groups: ADAMTS-5 mAb, IgG2c isotype control mAb, or no injection. Mice received injections 1×/week (10 mg/kg, i.p.) beginning at week 4 and continuing to week 8 or 16 after DMM surgery. DRG = dorsal root ganglion.
Figure 2
Figure 2
A) Total cartilage degeneration score in the medial compartment, #p=0.015 DMM+4 vs DMM+TS5+16; ##p=0.0014 DMM+4 vs DMM+IGG+16; *p=0.0116 DMM+IGG+8 vs DMM+IGG+16; ###p=0.0002 DMM+4 vs DMM+16; *p=0.0149 DMM+8 vs DMM+16; B) Medial tibial cartilage degeneration score, #p=0.0319 DMM+4 vs DMM+TS5+16; ##p=0.0046 DMM+4 vs DMM+IGG+16; *p=0.0119 DMM+IGG+8 vs DMM+IGG+16; ###p=0.0007 DMM+4 vs DMM+16; *p=0.013 DMM+8 vs DMM+16; C) Medial femoral cartilage degeneration score, #p=0.0188 DMM+4 vs DMM+TS5+16; ##p=0.002 DMM+4 vs DMM+IGG+16; *p=0.0299 DMM+IGG+8 vs DMM+IGG+16; ###p=0.0003 DMM+4 vs DMM+16; *p=0.0333 DMM+8 vs DMM+16; D) Osteophyte width, *p=0.0208 DMM+IGG+8 vs DMM+IGG+16; #p=0.0496 DMM+4 vs DMM+16; and E) Subchondral bone score were assessed 4, 8, and 16 weeks post DMM surgery in mice that were untreated (DMM), treated with IgG2c isotype control mAb (IgG), or treated with ADAMTS-5 mAb (TS5). Whiskers = 5-95 percentile; n=7-12 (details in Materials and Methods). Bar shows p-value for comparisons among treatment groups at a particular time point. F-H) Representative histology images of the medial knee joint compartment from mice 16 weeks after DMM surgery receiving F) no treatment, G) IgG isotype control Ab, or H) ADAMTS5 mAb starting 4 weeks after DMM. Images were chosen for mice representing the median histology scores from each treatment group based on the measures quantified in Figure 2A,D,E. In part F, arrows indicate medial femoral and tibial cartilage degeneration, an asterisk indicates tibial subchondral bone sclerosis, and the arrowhead indicates a tibial osteophyte. Scale bar = 0.5 mm.
Figure 3
Figure 3
Mechanical allodynia was assessed in mice that were untreated (DMM), treated with IgG2c isotype control mAb (+IgG2c), or treated with ADAMTS-5 mAb (+anti-ADAMTS-5) through 16 weeks after surgery (A). A decrease in withdrawal threshold from the baseline at time 0 indicates development of mechanical allodynia. A subset of mice (n=5) was tested 24 hours after the first injection to rule out an acute analgesic effect (B). mean+95%CI. DMM+anti-ADAMTS-5 vs DMM: +7 weeks, p=0.0051; +9 weeks, p=0.0001; +11 weeks, p=0.0109. DMM+anti-ADAMTS-5 vs DMM+IgG2c: +7 weeks, p<0.0001; +9 weeks, p<0.0001; +11 weeks, p=0.0024; black vs DMM; grey vs DMM+IgG2c.
Figure 4
Figure 4
Eight weeks after surgery, DRG cells were cultured from mice that were untreated (DMM), treated with IgG2c isotype control mAb (+IgG2c), or treated with ADAMTS-5 mAb (+anti-ADAMTS-5), and supernatants were analyzed for MCP-1 protein. mean±95%CI. **p=0.0056, ***p=0.0005. Dots represent individual wells. Plot shows the result of one out of two independent experiments (Expt 1).

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