title: Mitochondrial-derived reactive oxygen species (ROS) play a causal role in aging-related intervertebral disc degeneration.
abstract: Oxidative damage is a well-established driver of aging. Evidence of oxidative stress exists in aged and degenerated discs, but it is unclear how it affects disc metabolism. In this study, we first determined whether oxidative stress negatively impacts disc matrix metabolism using disc organotypic and cell cultures. Mouse disc organotypic culture grown at atmospheric oxygen (20% O(2)) exhibited perturbed disc matrix homeostasis, including reduced proteoglycan synthesis and enhanced expression of matrix metalloproteinases, compared to discs grown at low oxygen levels (5% O(2)). Human disc cells grown at 20% O(2) showed increased levels of mitochondrial-derived superoxide anions and perturbed matrix homeostasis. Treatment of disc cells with the mitochondria-targeted reactive oxygen species (ROS) scavenger XJB-5-131 blunted the adverse effects caused by 20% O(2). Importantly, we demonstrated that treatment of accelerated aging Ercc1(-/Δ) mice, previously established to be a useful in vivo model to study age-related intervertebral disc degeneration (IDD), also resulted in improved disc total glycosaminoglycan content and proteoglycan synthesis. This demonstrates that mitochondrial-derived ROS contributes to age-associated IDD in Ercc1(-/Δ) mice. Collectively, these data provide strong experimental evidence that mitochondrial-derived ROS play a causal role in driving changes linked to aging-related IDD and a potentially important role for radical scavengers in preventing IDD.
authors: Ferguson Laboratory for Orthopaedic Research, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors: Luigi A
authors: LA
authors: Nasto
authors: Andria R
authors: AR
authors: Robinson
authors: Kevin
authors: K
authors: Ngo
authors: Cheryl L
authors: CL
authors: Clauson
authors: Qing
authors: Q
authors: Dong
authors: Claudette
authors: C
authors: St Croix
authors: Gwendolyn
authors: G
authors: Sowa
authors: Enrico
authors: E
authors: Pola
authors: Paul D
authors: PD
authors: Robbins
authors: James
authors: J
authors: Kang
authors: Laura J
authors: LJ
authors: Niedernhofer
authors: Peter
authors: P
authors: Wipf
authors: Nam V
authors: NV
authors: Vo
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D055959:Intervertebral Disc Degeneration / Q000378:metabolism* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010100:Oxygen / Q000494:pharmacology; D011509:Proteoglycans / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D006025:Glycosaminoglycans; D011509:Proteoglycans; D017382:Reactive Oxygen Species; C523959:XJB-5-131; D020782:Matrix Metalloproteinases; D010100:Oxygen
references: Biochem Pharmacol. 2007 Sep 15;74(6):801-9
references: 17601494
references: Ageing Res Rev. 2007 Oct;6(3):247-61
references: 17870673
references: Nature. 2006 Dec 21;444(7122):1038-43
references: 17183314
references: Biochem J. 2006 Oct 1;399(1):29-35
references: 16787390
references: J Orthop Res. 2010 Dec;28(12):1600-7
references: 20973062
references: Spine (Phila Pa 1976). 2007 Dec 1;32(25):2827-33
references: 18246004
references: Biochem J. 1998 Feb 15;330 ( Pt 1):345-51
references: 9461529
references: Spine (Phila Pa 1976). 2001 Sep 1;26(17):1873-8
references: 11568697
references: Ann N Y Acad Sci. 2007 Jan;1096:239-48
references: 17405935
references: Spine (Phila Pa 1976). 2007 Dec 1;32(25):2812-9
references: 18246002
references: Nat Neurosci. 2012 Oct;15(10):1407-13
references: 22922784
references: Osteoarthritis Cartilage. 2005 Jul;13(7):614-22
references: 15979014
references: Spine (Phila Pa 1976). 2008 Nov 15;33(24):2586-95
references: 19011540
references: Spine (Phila Pa 1976). 2006 Aug 15;31(18):2151-61
references: 16915105
references: Mech Ageing Dev. 2004 Oct-Nov;125(10-11):811-26
references: 15541775
references: J Pharm Pharmacol. 2008 Aug;60(8):969-76
references: 18644190
references: Spine (Phila Pa 1976). 2005 Mar 1;30(5):487-96
references: 15738779
references: J Immunol. 1990 Jul 15;145(2):690-6
references: 2114447
references: Spine J. 2011 Feb;11(2):139-46
references: 21296298
references: Spine (Phila Pa 1976). 2009 May 15;34(11):1127-33
references: 19407676
references: Free Radic Biol Med. 2010 Mar 1;48(5):642-55
references: 20036736
references: Biotech Histochem. 2008 Oct;83(5):239-45
references: 19016368
references: Cell Rep. 2012 Nov 29;2(5):1137-42
references: 23122961
references: Spine (Phila Pa 1976). 2011 Oct 1;36(21):E1373-84
references: 21587103
references: Mol Cell Proteomics. 2009 Jan;8(1):172-89
references: 18784066
references: J Biol Chem. 2000 Dec 15;275(50):39027-31
references: 10976109
references: Biochim Biophys Acta. 1986 Sep 4;883(2):173-7
references: 3091074
references: Aging (Milano). 1998 Apr;10(2):144-6
references: 9666197
references: Int J Biochem Cell Biol. 2008;40(2):176-80
references: 18023240
references: Methods. 2001 Dec;25(4):402-8
references: 11846609
references: Spine (Phila Pa 1976). 1995 Jan 1;20(1):11-9
references: 7709270
references: Spine (Phila Pa 1976). 2001 Dec 1;26(23):2550-7
references: 11725235
references: J Pathol. 2002 Jul;197(3):286-92
references: 12115873
references: J Am Chem Soc. 2005 Sep 14;127(36):12460-1
references: 16144372
references: Biochem Soc Trans. 2002 Nov;30(Pt 6):869-74
references: 12440935
references: Spine (Phila Pa 1976). 2002 Dec 1;27(23):2631-44
references: 12461389
references: Spine (Phila Pa 1976). 1988 Feb;13(2):173-8
references: 3406837
references: Spine J. 2008 May-Jun;8(3):449-56
references: 18455111
references: Spine (Phila Pa 1976). 1997 May 15;22(10):1065-73
references: 9160463