Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis R.E. Miller, P.B. Tran,

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Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis R.E. Miller, P.B. Tran, S. Ishihara, J. Larkin, A.M. Malfait Osteoarthritis and Cartilage Volume 24, Issue 2, Pages 299-306 (February 2016) DOI: 10.1016/j.joca.2015.09.005 Copyright © 2015 Osteoarthritis Research Society International Terms and Conditions

Fig. 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. Osteoarthritis and Cartilage 2016 24, 299-306DOI: (10.1016/j.joca.2015.09.005) Copyright © 2015 Osteoarthritis Research Society International Terms and Conditions

Fig. 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 Fig. 2(A, 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. Osteoarthritis and Cartilage 2016 24, 299-306DOI: (10.1016/j.joca.2015.09.005) Copyright © 2015 Osteoarthritis Research Society International Terms and Conditions

Fig. 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 h 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; gray vs DMM + IgG2c. Osteoarthritis and Cartilage 2016 24, 299-306DOI: (10.1016/j.joca.2015.09.005) Copyright © 2015 Osteoarthritis Research Society International Terms and Conditions

Fig. 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). Osteoarthritis and Cartilage 2016 24, 299-306DOI: (10.1016/j.joca.2015.09.005) Copyright © 2015 Osteoarthritis Research Society International Terms and Conditions