Experimental and Molecular Medicine

Korean Society for Biochemistry and Molecular Biongy (생화학분자생물학회)
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Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300

  • Sacitharan, Pradeep K. (Botnar Research Centre, University of Oxford) ;
  • Lwin, Seint (Botnar Research Centre, University of Oxford) ;
  • Gharios, George Bou (The Institute of Ageing and Chronic Disease, University of Liverpool) ;
  • Edwards, James R. (Botnar Research Centre, University of Oxford)
  • Received : 2018.03.20
  • Accepted : 2018.06.12
  • Published : 2018.09.30
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Abstract

Ageing is the primary risk factor for osteoarthritis (OA). A decline in the ageing-associated process of autophagy is suggested as a potential contributor to OA development. Polyamines such as spermidine decrease during ageing, contributing to impaired autophagy and reduced cellular function. However, the role of polyamines and their effect on the regulatory mechanism governing autophagy in aged and arthritic cartilage tissue has not been established. Elucidating if polyamine regulation of autophagy is impaired during ageing and OA in chondrocytes may lead to improved treatment approaches to protect against cartilage degradation. Our results indicate that polyamine synthesis was decreased in aged and OA cartilage, along with reduced autophagy activity, evidenced by decreased autophagy-related gene and protein expression and autophagosome formation. Importantly, spermidine treatment increased the expression of the acetyltransferase EP300, which binds to crucial autophagy proteins, Beclin1 and LC3, and elevates chondrocyte autophagy. Our data indicate spermidine prevents the ageing- and OA-related decrease in autophagy and may protect against OA development.

Keywords

References

  1. Glyn-Jones, S. et al. Osteoarthritis. Lancet 386, 376-387 (2015). https://doi.org/10.1016/S0140-6736(14)60802-3
  2. Wieland, H., Michaelis, M., Kirschbaum, B. J. & Rudolphi, K. Osteoarthritis - an untreatable disease? Nat. Rev. Drug. Discov. 4, 331-344 (2005). https://doi.org/10.1038/nrd1693
  3. Rubinsztein, D. C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682-695 (2011). https://doi.org/10.1016/j.cell.2011.07.030
  4. Carames, B., Taniguchi, N., Otsuki, S., Blanco, F. J. & Lotz, M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 62, 791-801 (2010).
  5. Carames, B., Olmer, M., Kiosses, W. B. & Lotz, M. K. The relationship of autophagy defects to cartilage damage during joint aging in a mouse model. Arthritis Rheumatol. 67, 1568-1576 (2015). https://doi.org/10.1002/art.39073
  6. Bouderlique, T. et al. Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. Ann. Rheum. Dis. 3, 627-631 (2015).
  7. Minois, N., Carmona-Gutierrez, D. & Madeo, F. Polyamines in aging and disease. Aging 3, 716-732 (2011). https://doi.org/10.18632/aging.100361
  8. Pietrocola, F. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509-516 (2015). https://doi.org/10.1038/cdd.2014.215
  9. Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305-1314 (2009). https://doi.org/10.1038/ncb1975
  10. Mizushima, N. Chapter 2 methods for monitoring autophagy using GFP-LC3 transgenic mice. Methods Enzymol. 451, 13-23 (2009).
  11. Burleigh, A. et al. Joint immobilization prevents murine osteoarthritis and reveals the highly mechanosensitive nature of protease expression in vivo. Arthritis Rheum. 64, 2278-2288 (2012). https://doi.org/10.1002/art.34420
  12. Tanida, I., Ueno, T. & Kominami, E. LC3 and autophagy. Methods Mol. Biol. 445, 77-88 (2008).
  13. Yang, Y. et al. Induction of autophagy by spermidine is neuroprotective via inhibition of caspase 3-mediated Beclin 1 cleavage. Cell Death Dis. 8, e2738 (2017). https://doi.org/10.1038/cddis.2017.161
  14. Suppola, S. et al. Overexpression of spermidine/spermine N1-acetyltransferase under the control of mouse metallothionein I promoter in transgenic mice: evidence for a striking post-transcriptional regulation of transgene expression by a polyamine analogue. Biochem. J. 338(Pt 2), 311-316 (1999). https://doi.org/10.1042/bj3380311
  15. Carames, B. et al. Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann. Rheum. Dis. 71, 575-581 (2012). https://doi.org/10.1136/annrheumdis-2011-200557
  16. Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 7, 1432-1440 (2014).
  17. Baroja-Mazo, A., Revilla-Nuin, B., Ramirez, P. & Pons, J. A. Immunosuppressive potency of mechanistic target of rapamycin inhibitors in solid-organ transplantation. World J. Transplant. 6, 183-192 (2016). https://doi.org/10.5500/wjt.v6.i1.183
  18. Li, J., Kim, S. G. & Blenis, J. Rapamycin: one drug, many effects. Cell. Metab. 19, 373-379 (2014). https://doi.org/10.1016/j.cmet.2014.01.001
  19. Casero, R. A. & Marton, L. J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat. Rev. Drug. Discov. 6, 373-390 (2007). https://doi.org/10.1038/nrd2243
  20. Lin, S. Y. et al. GSK3-TIP60-ULK1 signaling pathway links growth factor deprivation to autophagy. Science 336, 477-481 (2012). https://doi.org/10.1126/science.1217032
  21. Chrisam, M. et al. Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice. Autophagy 11, 2142-2152 (2015). https://doi.org/10.1080/15548627.2015.1108508
  22. Buttner, S. et al. Spermidine protects against ${\alpha}$-synuclein neurotoxicity. Cell Cycle 13, 3903-3908 (2014). https://doi.org/10.4161/15384101.2014.973309
  23. Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8(+) T cell formation. eLife 3, e03706 (2014). https://doi.org/10.7554/eLife.03706

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