Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis L. Habouri, F.E. El Mansouri, Y.

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Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis L. Habouri, F.E. El Mansouri, Y. Ouhaddi, B. Lussier, J.-P. Pelletier, J. Martel-Pelletier, M. Benderdour, H. Fahmi Osteoarthritis and Cartilage Volume 25, Issue 10, Pages 1719-1728 (October 2017) DOI: 10.1016/j.joca.2017.07.001 Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Expression of 12/15-LOX during the progression of DMM-induced OA and aging in WT mice. Knee joint sections from sham- and DMM-operated mice at 2, 4 or 8 weeks post-surgery (A) and from 3-, 6-, 9- and 15-month-old mice (B) (n = 5 in each group) were analyzed by immunohistochemistry for 12/15-LOX as described in the Materials and Methods section. Each image shown is one representative section selected from 20 sections of an experimental group (4 sections from each knee joint and 5 knee joints in each experimental group). (C, D) Percentage of chondrocytes expressing 12/15-LOX. Data are presented as median with interquartile range (n = 5 per group). The P-values were calculated using the Kruskal–Wallis test followed by Dunn's multiple comparisons test. (E, F) Expression of 12/15-LOX mRNA during the progression of DMM-induced OA and aging. Results are expressed as -fold change, considering 1 as the value of sham-operated (E) or 3-month-old (F) mice. Horizontal lines on the graph represent the mean of 2 independent experiments, each involving 5 mice per group. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Deletion of 12/15-LOX accelerated cartilage erosion with age. Coronal sections of whole knee joints from WT (A) and 12/15-LOX−/− (B) mice at ages 3 months, 6 months, and 9 months (n = 6 mice per group) were prepared and stained with Safranin O–fast green to assess the integrity of articular cartilage. Each image shown is one representative section selected from 48 sections of an experimental group (8 sections from each knee joint and 6 knee joints in each experimental group). The representative section was selected based on the average score from each group. (Original magnification ×40 in the upper panels (scale bars = 500 μM); and ×100 in the lower panels (scale bars = 200 μM)). (C) Summed histologic scores of knee cartilage from WT mice (open symbols) and 12/15-LOX−/− mice (filled symbols) at ages 3, 6, and 9 months as determined using the OARSI scoring system. Data are presented as median with interquartile range (n = 6 per group). P values were determined by Mann–Whitney U test. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Deficiency of 12/15-LOX exacerbated cartilage erosion after DMM surgery. Ten-week-old WT mice (A) and 12/15-LOX−/− mice (B) (n = 8 mice per group) were subjected to DMM surgery. Knee joint samples were harvested 2, 4, or 8 weeks post-surgery, prepared and stained with Safranin O–fast green to assess the extent of articular cartilage degeneration. Each image shown is one representative section selected from 64 sections of an experimental group (8 sections from each knee joint and 8 knee joints in each experimental group). The representative section was selected based on the average score from each experimental group. (Original magnification ×40 in the upper panels (scale bars = 500 μM); and ×100 in the lower panels (scale bars = 200 μM)). (C) Summed histologic scores of knee cartilage from WT (open symbols) and 12/15-LOX−/− (filled symbols) mice at 2, 4, and 8 weeks after DMM surgery, as determined using the OARSI scoring system. Data are presented as median with interquartile range (n = 8 per group). P values were determined by Mann–Whitney U test. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Expression of MMP-13, ADAMTS5, iNOS and mPGES-1 in the knee joints of WT and 12/15-LOX−/− mice at 3 and 6 months old. Knee joint sections from 3-, (n = 4 mice per genotype) and 6-month-old mice (n = 5 mice per genotype) were analyzed by immunohistochemistry for MMP-13, ADAMTS5, iNOS and mPGES-1 (A) as described in the Materials and Methods section. Each image shown is one representative section selected from 16–20 sections of an experimental group (4 sections from each knee joint and 4–5 knee joints in each experimental group). (B) Percentage of chondrocytes expressing MMP-13, ADAMTS5, iNOS and mPGES-1 in WT (open symbols) and 12/15-LOX−/− (filled symbols) mice. Data are presented as median with IQR of each group. P values were determined by Mann–Whitney U test. (C) Expression of MMP-13, ADAMTS5, iNOS and mPGES-1 mRNA in WT (open bars) and 12/15-LOX−/− mice (solid bars) at 3 and 6 months of age. The results are expressed as fold change considering 1 as the value of control (i.e., 3-month-old WT mice). Horizontal lines on the graph represent the mean of 2 independent experiments, each involving 5 mice per group. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Expression of MMP-13, ADAMTS5, iNOS and mPGES-1 in the knee joints of 12/15-LOX−/− mice at 2 weeks post-DMM surgery. Knee joint sections from sham- (n = 4 per genotype) and DMM-operated (n = 5 per genotype) mice at 2 weeks post-surgery were analyzed by immunohistochemistry for MMP-13, ADAMTS5, iNOS and mPGES-1 (A) as described in the Materials and Methods section. Each image shown is one representative section selected from 16–20 sections of an experimental group (4 sections from each knee joint and 4–5 knee joints in each experimental group). (B) Percentage of chondrocytes expressing ADAMTS5, MMP-13, iNOS and mPGES-1. Data are presented as median with IQR of each group. P values were determined by Mann–Whitney U test. (C) Expression of ADAMTS5, MMP-13, iNOS and mPGES-1 mRNA in WT (open bars) and 12/15-LOX−/− (solid bars) mice at 2 weeks post-sham or -DMM surgery. The results are expressed as fold change considering 1 as the value of control (i.e., sham-operated WT mice). Horizontal lines on the graph represent the mean of 2 independent experiments, each involving 5 mice per group. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 12/15-LOX metabolites prevented IL-1α-induced inflammatory and catabolic responses in cultured cartilage explants. Femoral heads from 3- to 4-week-old WT mice were cultured as explants (6 femoral heads (3 mice) per well) in 24-well plates and were stimulated with 1 ng/ml IL-1α in the absence or presence of 13-HODE (5 μM), 15-HETE (5 μM) and LXA4 (0.5 μM) for 48 h. The activity of MMP-13 (Fluorescence 490, 520 nm) (A), and the levels of NO (B) and PGE2, (C) in conditioned media were determined. Data are expressed as the mean ± SD of three independent experiments. *P < 0.05 compared with IL-1α-treated cartilage. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 7 LXA4 attenuated DMM-induced cartilage destruction. Ten-week-old WT mice were subjected to DMM (n = 14) or sham (n = 14) surgery. DMM-operated mice were intraperitoneally injected with either vehicle control (PBS) or LXA4 (5 μg/kg/day) (n = 7 mice per group) every day beginning 1 day after surgery, for 8 weeks. Sham-operated mice also received LXA4 or vehicle control (n = 7 mice per group). Knee joints were collected and cartilage degradation was analyzed using Safranin O-fast green staining. (A) Representative images are shown. The representative section was selected based on the average score from each experimental group. (B) Summed histologic scores, as determined using the OARSI scoring system. Data are presented as median with IQR for each group. P values were determined by Mann–Whitney U test. Osteoarthritis and Cartilage 2017 25, 1719-1728DOI: (10.1016/j.joca.2017.07.001) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions