Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation K.M. Larson,

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Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation K.M. Larson, L. Zhang, G.J. Badger, G.D. Jay Osteoarthritis and Cartilage Volume 25, Issue 9, Pages 1488-1495 (September 2017) DOI: 10.1016/j.joca.2017.05.012 Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 COF values at 0, 15, 30, 45, and 60 min cycling time for mouse knees evaluated with a whole joint pendulum system. Regression lines and mean ± SE are plotted for each experimental group: GT/GT recombined at 7 days (yellow triangle), GT/GT recombined at 14 days of age (green diamond), GT/GT not recombined (red triangle), lubricin wild type (purple circle), and lubricin heterozygous mice (blue square). Significant increases in COF were observed for both GT/GT recombined at day 7 (P < 0.001) and day 14 (P < 0.001). Osteoarthritis and Cartilage 2017 25, 1488-1495DOI: (10.1016/j.joca.2017.05.012) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Joint histopathology scoring was used to evaluate OA damage for mouse knees, following whole joint pendulum friction testing. GT/GT mice recombined at 7 days of age (GTR7D/GTR7D), GT/GT mice recombined at 14 days (GTR14D/GTR14D) of age, and GT/GT mice not recombined (GT/GT) display significantly higher OA damage scores compared to lubricin wild type (+/+) and lubricin heterozygous (+/−) mice (***P < 0.001 for all comparisons). Thus, GTR7D/GTR7D and GTR14D/GTR14D test groups display joint histopathology similar to the lubricin-null phenotype, GT/GT mice. Osteoarthritis and Cartilage 2017 25, 1488-1495DOI: (10.1016/j.joca.2017.05.012) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Electron micrographs were used to qualitatively assess the superficial zone of the medial femoral condyle of Prg4 expressing and Prg4 GT mouse knees at 14 days after birth. Collagen fiber alignment was stained with tannic acid in black. The lubricin-null GT not recombined (GT/GT) has disrupted collagen fiber alignment compared to the normal lubricin wild type (+/+) control. GT/GT mice recombined at 2 days (GTR2D/GTR2D) and 7 days after birth (GTR7D/GTR7D) display more parallel collagen fiber alignment similar to the +/+ mice but less collagen density (as evident through the gray vs black coloring of the collagen at the articular surface). GT/GT cartilage displayed a thicker collagen structure along with collagen disruption compared to the +/+ cartilage. This thickening is seen to some extent in GTR2D/GTR2D and GTR7D/GTR7D but not to the same extent as the GT/GT cartilage that had not been recombined. An amorphous lamina splendens surface layer, demarcated by black triangles, sits atop the collagen type II fibers. Images were taken at ×13500 and scale bar is 0.2 microns. Osteoarthritis and Cartilage 2017 25, 1488-1495DOI: (10.1016/j.joca.2017.05.012) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Prg4 GT mouse knees, following whole joint pendulum friction testing, display reduced caspase-3 activation upon recombination. GT/GT mice recombined at 7 days of age (GTR7D/GTR7D), GT/GT mice recombined at 14 days (GTR14D/GTR14D) of age, lubricin heterozygous mice (+/−), and lubricin wild type mice (+/+) have significantly lower caspase-3 positive cells compared to the lubricin-null (GT/GT) mice (**P = 0.003, ***P < 0.001, *P = 0.025). The GTR7D/GTR7D and GTR14D/GTR14D test groups, despite being born lubricin-null, display levels of caspase-3 positivity similar to levels of lubricin producing mice. Osteoarthritis and Cartilage 2017 25, 1488-1495DOI: (10.1016/j.joca.2017.05.012) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Peroxynitrite concentrations were assayed for the femoral head cartilage of GT mice recombined at day 7 (GTR7D/GTR7D) and 14 (GTR14D/GTR14D) after birth. All testing groups, GTR7D/GTR7D and GTR14D/GTR14D, as well as the lubricin wild type (+/+) and heterozygous (+/−) controls had significantly lower peroxynitrite content compared to the lubricin-null (GT/GT) mice (***P < 0.001 for all) respectively. There were also significant differences between GTR7D/GTR7D and GTR14D/GTR14D mice compared to the +/+ mice (*P = 0.035, **P = 0.002). Osteoarthritis and Cartilage 2017 25, 1488-1495DOI: (10.1016/j.joca.2017.05.012) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 Immunohistochemistry of HA in mouse tibio-femoral joints, following whole joint pendulum friction testing. A) HA accumulated more on the surface of tissues that were lubricin deficient. Lubricin wild type mice (+/+) exhibited lower quantities of HA accumulation on the articular and synovial surfaces. Lubricin-null (GT/GT), GT mice recombined at day 7 (GTR7D/GTR7D), and GT mice recombined at day 14 (GTR14D/GTR14D) displayed much thicker and vibrant HA accumulation at the articular and synovial surfaces. B) Quantification of HA expressed as optical density. Lubricin-null (GT/GT), GT mice recombined at day 7 (GTR7D/GTR7D), and GT mice recombined at day 14 (GTR14D/GTR14D) displayed significantly higher optical density values for HA accumulation in the mouse tibio-femoral joint compared to lubricin wild type mice (+/+) (*P = 0.02, **P = 0.009). Osteoarthritis and Cartilage 2017 25, 1488-1495DOI: (10.1016/j.joca.2017.05.012) Copyright © 2017 Osteoarthritis Research Society International Terms and Conditions