J. J. McDougall, S. Albacete, N. Schuelert, P. G. Mitchell, C. Lin, J

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Lysophosphatidic acid provides a missing link between osteoarthritis and joint neuropathic pain J.J. McDougall, S. Albacete, N. Schuelert, P.G. Mitchell, C. Lin, J.L. Oskins, H.H. Bui, M.G. Chambers Osteoarthritis and Cartilage Volume 25, Issue 6, Pages 926-934 (June 2017) DOI: 10.1016/j.joca.2016.08.016 Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Concentration of LPA in human synovial fluid taken from normal knees as well as knees with either mild, moderate or severe OA. Intra-articular LPA levels rose as OA severity increased. (****P < 0.0001 one-way ANOVA with Dunnett's post hoc test). Data are means ± S.E.M. (n = 11–21 patients/group). Osteoarthritis and Cartilage 2017 25, 926-934DOI: (10.1016/j.joca.2016.08.016) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 (A): Electron micrographs of saphenous nerve sections taken from rats treated with either vehicle, LPA, or a combination of LPA and the LPA antagonist Ki-16425. Myelin sheath thickness decreased at day 21 following LPA administration which was inhibited by co-administration of Ki-16425. (B): G-ratio calculations showing that LPA caused significant demyelination (i.e., greater G-ratio value) which could be blocked by co-injection of Ki-16425. (***P < 0.001 one-way ANOVA with Tukey's post hoc test). Data are means ± S.E.M. (n = 321–581 neurones from three animals). Osteoarthritis and Cartilage 2017 25, 926-934DOI: (10.1016/j.joca.2016.08.016) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 (A): Immunohistochemical micrographs of DRGs stained with the nerve injury marker ATF-3. Cell bodies were harvested at day 21 from control (vehicle), LPA, and LPA + the LPA1 receptor antagonist Ki-16425 treated animals. (B): Percentage of DRGs that stained positive for ATF-3 was increased in LPA-treated rats. This neurodegenerative effect was blocked by Ki-16425. (*P < 0.05 Kruskal–Wallis test with Dunn's multiple comparisons test). Data are means ± S.E.M. (n = 180–295 sections from three animals). Osteoarthritis and Cartilage 2017 25, 926-934DOI: (10.1016/j.joca.2016.08.016) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 (A): Reduction in saphenous nerve conduction velocity following LPA treatment indicative of demyelination. (*P < 0.05, unpaired Student t-test). (B): Firing frequency of joint afferents in response to knee rotation by different levels of torque. Compared to vehicle, LPA increased joint mechanosensitivity, but only during hyper-rotation of the knee. (**P.0.01 Two-way ANOVA with Bonferroni post hoc test). Data are means ± S.E.M. (n = 8–9 rats). Osteoarthritis and Cartilage 2017 25, 926-934DOI: (10.1016/j.joca.2016.08.016) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 (A): Time-course showing a weight bearing deficit in response to intra-articular injection of different doses of LPA compared to vehicle treated knees. (B): Inhibition of the pro-nociceptive effect of LPA by pre-treatment of animals with Ki-16425 (****P < 0.0001 one-way ANOVA). Data are means ± S.E.M. (n = 5 rats/group). Osteoarthritis and Cartilage 2017 25, 926-934DOI: (10.1016/j.joca.2016.08.016) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 Treatment of MIA rats with Ki-16425 reduced saphenous nerve g-ratio measurements (A), DRGs ATF-3 expression (B), and pain behaviour (C) indicating an anti-neuropathic effect of LPA receptor blockade in OA joints. By day 71, MIA rats exhibited a robust pain response which was unresponsive to diclofenac treatment, but could be inhibited by Ki-16425 (D). (*P < 0.05, ***P < 0.001, ****P < 0.0001 Student's t-test or Mann–Whitney test). Data are means ± S.E.M. Osteoarthritis and Cartilage 2017 25, 926-934DOI: (10.1016/j.joca.2016.08.016) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions