Inhibition of caspase-9 reduces chondrocyte apoptosis and proteoglycan loss following mechanical trauma C.A.M. Huser, M.Sc., M. Peacock, M.E. Davies,

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Inhibition of caspase-9 reduces chondrocyte apoptosis and proteoglycan loss following mechanical trauma C.A.M. Huser, M.Sc., M. Peacock, M.E. Davies, Ph.D. Osteoarthritis and Cartilage Volume 14, Issue 10, Pages 1002-1010 (October 2006) DOI: 10.1016/j.joca.2006.03.012 Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 1 TEM photomicrographs of individual chondrocytes in sections of superficial cartilage explants cultured for 48h. (A) Healthy chondrocyte in unimpacted control (5000×). (B) Apoptotic chondrocyte in an impacted cartilage explant (6000×), showing evidence of nuclear blebbing (*) and apoptotic bodies (arrows). N=nucleus. Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 2 Representative histological sections of cartilage explants incubated with the specific caspase-3 substrate PhiPhiLux G1D2 (green), and counterstained with DAPI (blue), after 12h of culture. A and B are unimpacted controls, C and D were impacted. A and C are merge images of DAPI and PhiPhiLux signals, B and D are PhiPhiLux G1D2 signal only. White arrows point to cells where caspase-3 is active. Original magnification 400×. Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 3 Representative histological sections of cartilage explants showing effect of a single-impact load and subsequent culture for 48h on chondrocyte death. TUNEL-positive cells appear dark blue (dead), and live cells appear pink due to safranin ‘O’ nuclear counterstain. (A) Unimpacted control. (B–E) Impacted from 50mm, and pre-incubation with DMEM (B), caspase-3 (C), caspase-8 (D) and caspase-9 (E) inhibitors 3h prior to impact. Original magnification 500×. Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 4 Effect of a single-impact load and pre-incubation with specific inhibitors of caspase-3 (C3), caspase-8 (C8) and caspase-9 (C9) on the percentage of TUNEL-positive chondrocytes in the superficial zone after 48h in culture. *Represents a significant difference from 0mm non-impacted control , and #represents a significant difference from 50 mm impacted, untreated control (P<0.05). Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 5 Effect of a single-impact load and pre-incubation with inhibitors of caspase-3 (C3), caspase-8 (C8) and caspase-9 (C9) on the percentage weight gain of cartilage explants after 48h in culture. *Represents a significant difference from 0mm non-impacted control (P<0.05). Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 6 Effect of a single-impact load and pre-incubation with inhibitors of caspase-3 (C3), caspase-8 (C8) and caspase-9 (C9) on the amount of GAG released into the media (μg/mg of cartilage) after 48h in culture. *Represents a significant difference from 0mm non-impacted control (P<0.05). Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions

Fig. 7 Sequence of cellular events leading to apoptosis-like chondrocyte death following a single-impact load in equine articular cartilage explants, as hypothesised from results obtained in this study. A single-impact load leads to yet undetermined cellular stress, which results in caspase-9 activation. Caspase-9 then activates the effector caspase-3, which directly causes apoptosis-like cell death. Osteoarthritis and Cartilage 2006 14, 1002-1010DOI: (10.1016/j.joca.2006.03.012) Copyright © 2006 OsteoArthritis Research Society International Terms and Conditions