Depletion of gangliosides enhances cartilage degradation in mice

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Depletion of gangliosides enhances cartilage degradation in mice F. Sasazawa, T. Onodera, T. Yamashita, N. Seito, Y. Tsukuda, N. Fujitani, Y. Shinohara, N. Iwasaki Osteoarthritis and Cartilage Volume 22, Issue 2, Pages 313-322 (February 2014) DOI: 10.1016/j.joca.2013.11.015 Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Schematic of the GSL synthetic pathway in mammalian cells. GSLs from ceramide through glucosylceramide (GlcCer) are synthesized by GlcCer synthase, encoded by the Ugcg locus. Lactosylceramide (LacCer) is the key branching point of GSL biosynthesis, with four alternate pathways (lacto-series, neo lacto-series, globo-series, and isoglobo-series) branching off from LacCer. Virtually all the ganglio-series GSLs (gangliosides) are detected as a-series and b-series gangliosides, both of which are synthesized from the shared precursor molecule GM3, itself the product of GM3 synthase (GM3S, encoded by the GM3S locus). The o-series gangliosides typically are detected only in trace amounts. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Histologic features of WT and GM3S−/− mice with OA -inducing procedures. A, Histologic findings of age-associated OA in WT and GM3S−/− mice. HE staining and Safranin O (Saf-O) staining are shown for each genotype at 4 months and at 15 months of age. Bars = 50 μm. B, Histologic findings of instability-induced OA in WT and GM3S−/− mice. HE staining and Saf-O staining are shown for each genotype at 8 weeks after knee operation. Bars = 50 μm. C, HE staining of whole knee joints from instability-induced model mice. Bars = 500 μm. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Cartilage degradation induced by interleukin-1α (IL-1α) stimulation. A, Histologic findings in cartilage explants from WT and GM3S−/− mice, cultured with IL-1α and subjected to Safranin O (Saf-O) staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and MMP-13 immunostaining. Bars = 10 μm. B, TUNEL-positive cell ratio in cultured cartilage explants from WT and GM3S−/− mice (n = 6). C, MMP-13-positive cell ratio in cultured cartilage explants from WT and GM3S−/− mice (n = 6). D, Proteoglycan release in cultured cartilage explants from WT and GM3S−/− mice (n = 4 samples (eight mice) per group). E, Quantification of MMP-13 release in mouse femoral head culture supernatant, as determined by ELISA (GM3S−/−: n = 5 samples (10 mice) and WT: n = 8 samples (16 mice) per group). B–E, Values are the means and 95% CI. **: P < 0.01 vs WT mice. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 Relative gene expression for genes encoding MMP-13 (A) and ADAMTS-5 (B) at the indicated time points after stimulation with IL-1α. Quantitative real-time reverse transcription–polymerase reaction analysis was performed in chondrocytes from WT and GM3S−/− mice cultured with or without IL-1α (shown in the graph as (+) and (−), respectively). The mRNA expression levels of each target gene are normalized to the cycle threshold of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-encoding transcript. Values are the means and 95% CI (n = 3). **: P < 0.01 vs WT mice. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 Association of the overexpression of the gene encoding GM3 synthase (GM3S) with down-regulated expression of the genes encoding MMP-13 and ADAMTS-5 in response to stimulation with interleukin-1α (IL-1α) in chondrocytes from WT mice. A, GM3S mRNA expression in the chondrocytes was up-regulated at 48 h after transfection. B, C, Chondrocytes overexpressing GM3S and stimulated with IL-1α had significantly suppressed levels of MMP-13 – (B) and ADAMTS-5 – (C) encoding mRNA, as compared with those in chondrocytes without overexpression and without IL-1α stimulation. The mRNA expression values of each target gene are normalized to the cycle threshold of the GAPDH-encoding transcript. Values are the means and 95% CI (n = 3). *: P < 0.05, and **: P < 0.01. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 Quantification by MS of GSLs in cultured mouse chondrocyte pellets. Time-dependent changes of GSL amounts in cultured chondrocytes are shown at the indicated time points after stimulation with IL-1α. The levels of gangliosides were significantly higher than those of the globo-series and (neo)lacto-series at almost all the time points. Values are the means and 95% CI (n = 3). *: P < 0.05, and **: P < 0.01. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Fig. 7 Scheme of the effects of inhibition of GSL synthetic pathway. Gray shaded frame represents molecules absent in mice. A, WT mice. B, Ugcg−/− mice exhibit embryonic lethality6–8. C, GM3S−/− mice show OA development without apparent growth impairment. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Supplementary Fig. 1 Histologic scoring of whole knee joint of instability-induced OA models. Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions

Supplementary Fig. 2 Quantification of NO release in mouse femoral head culture supernatant, as determined by Griess reagent system (Promega). Values are the means and 95% CI (GM3S−/−: n = 5 samples (10 mice) and WT: n = 8 samples (16 mice) per group). Osteoarthritis and Cartilage 2014 22, 313-322DOI: (10.1016/j.joca.2013.11.015) Copyright © 2013 Osteoarthritis Research Society International Terms and Conditions