Browse > Article
http://dx.doi.org/10.1038/s12276-018-0173-3

Small molecule natural compound agonist of SIRT3 as a therapeutic target for the treatment of intervertebral disc degeneration  

Wang, Jianle (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Nisar, Majid (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Huang, Chongan (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Pan, Xiangxiang (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Lin, Dongdong (Department of Neurosurgery Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Zheng, Gang (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Jin, Haiming (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Chen, Deheng (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Tian, Naifeng (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Huang, Qianyu (Department of Anesthesiology and Operating Room, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Duan, Yue (Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University)
Yan, Yingzhao (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Wang, Ke (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Wu, Congcong (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Hu, Jianing (The Second School of Medicine, Wenzhou Medical University, Wenzhou Medical University)
Zhang, Xiaolei (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Wang, Xiangyang (Department of Orthopaedic Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University)
Publication Information
Experimental and Molecular Medicine / v.50, no.11, 2018 , pp. 5.1-5.14 More about this Journal
Abstract
Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of intervertebral disc degeneration (IVDD). Sirtuin 3 (SIRT3), a sirtuin family protein located in mitochondria, is essential for mitochondrial homeostasis; however, the role of SIRT3 in the process of IVDD has remained elusive. Here, we explored the expression of SIRT3 in IVDD in vivo and in vitro; we also explored the role of SIRT3 in senescence, apoptosis, and mitochondrial homeostasis under oxidative stress. We subsequently activated SIRT3 using honokiol to evaluate its therapeutic potential for IVDD. We assessed SIRT3 expression in degenerative nucleus pulposus (NP) tissues and oxidative stress-induced nucleus pulposus cells (NPCs). SIRT3 was knocked down by lentivirus and activated by honokiol to determine its role in oxidative stress-induced NPCs. The mechanism by which honokiol affected SIRT3 regulation was investigated in vitro, and the therapeutic potential of honokiol was assessed in vitro and in vivo. We found that the expression of SIRT3 decreased with IVDD, and SIRT3 knockdown reduced the tolerance of NPCs to oxidative stress. Honokiol ($10{\mu}M$) improved the viability of NPCs under oxidative stress and promoted their properties of anti-oxidation, mitochondrial dynamics and mitophagy in a SIRT3-dependent manner. Furthermore, honokiol activated SIRT3 through the AMPK-PGC-$1{\alpha}$ signaling pathway. Moreover, honokiol treatment ameliorated IVDD in rats. Our study indicated that SIRT3 is involved in IVDD and showed the potential of the SIRT3 agonist honokiol for the treatment of IVDD.
Keywords
Citations & Related Records
연도 인용수 순위
  • Reference
1 Salvatori, I., Valle, C., Ferri, A. & Carri, M. T. SIRT3 and mitochondrial metabolism in neurodegenerative diseases. Neurochem. Int. 109, 184 (2017).   DOI
2 Deyo, R. A. & Mirza, S. K. CLINICAL PRACTICE. Herniated lumbar intervertebral disk. N. Engl. J. Med. 374, 1763 (2016).   DOI
3 Dikalova, A. E. et al. Sirt3 impairment and SOD2 hyperacetylation in vascular oxidative stress and hypertension. Circ. Res. 121, 564-574 (2017).   DOI
4 Woodbury, A., Yu, S. P., Wei, L. & Garcia, P. Neuro-modulating effects of honokiol: a review. Front. Neurol. 4, 130 (2013).
5 Fried, L. E. & Arbiser, J. L. Honokiol, a multifunctional antiangiogenic and antitumor agent. Antioxid. Redox Signal. 11, 1139-1148 (2009).   DOI
6 Pillai, V. B. et al. Honokiol blocks and reverses cardiac hypertrophy in mice by activating mitochondrial Sirt3. Nat. Commun. 6, 6656 (2015).   DOI
7 General Assembly of the World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J. Am. Coll. Dent. 81, 14-18 (2014).
8 Pfirrmann, C. W., Metzdorf, A., Zanetti, M., Hodler, J. & Boos, N. Magnetic resonance classification of lumbar intervertebral disc degeneration. Spine 26, 1873 (2001).   DOI
9 Xu, D. et al. Hydrogen sulfide protects against endoplasmic reticulum stress and mitochondrial injury in nucleus pulposus cells and ameliorates intervertebral disc degeneration. Pharmacol. Res. 117, 357-369 (2017).   DOI
10 Zeng, Z. et al. Polydatin ameliorates injury to the small intestine induced by hemorrhagic shock via SIRT3 activation-mediated mitochondrial protection. Expert. Opin. Ther. Targets 20, 645 (2016).   DOI
11 Shi, H. et al. Sirt3 protects dopaminergic neurons from mitochondrial oxidative stress. Hum. Mol. Genet. 26, 1915-1926 (2017).   DOI
12 Chen, D. et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis. 7, e2441 (2016).   DOI
13 Vergroesen, P. P. et al. Mechanics and biology in intervertebral disc degeneration: a vicious circle. Osteoarthr. Cartil. 23, 1057-1070 (2015).   DOI
14 Fontana, G., See, E. & Pandit, A. Current trends in biologics delivery to restore intervertebral disc anabolism. Adv. Drug Deliv. Rev. 84, 146-158 (2015).   DOI
15 Dimozi, A., Mavrogonatou, E., Sklirou, A. & Kletsas, D. Oxidative stress inhibits the proliferation, induces premature senescence and promotes a catabolic phenotype in human nucleus pulposus intervertebral disc cells. Eur. Cell Mater. 30, 89-102 (2015). discussion 3.   DOI
16 Zhao, C. Q., Zhang, Y. H., Jiang, S. D., Jiang, L. S. & Dai, L. Y. Both endoplasmic reticulum and mitochondria are involved in disc cell apoptosis and intervertebral disc degeneration in rats. Age 32, 161-177 (2010).   DOI
17 Blanco, F. J., Rego, I. & Ruiz-Romero, C. The role of mitochondria in osteoarthritis. Nat. Rev. Rheumatol. 7, 161-169 (2011).   DOI
18 Osellame, L. D. & Duchen, M. R. Quality control gone wrong: mitochondria, lysosomal storage disorders and neurodegeneration. Br. J. Pharmacol. 171, 1958-1972 (2014).   DOI
19 Zemirli, N., Morel, E. & Molino, D. Mitochondrial dynamics in basal and stressful conditions. Int. J. Mol. Sci. 19, 564 (2018).   DOI
20 Han, B. et al. A simple disc degeneration model induced by percutaneous needle puncture in the rat tail. Spine 33, 1925 (2008).   DOI
21 Zhang, J. et al. Are sirtuins markers of ovarian aging? Gene 575, 680-686 (2016).   DOI
22 Wang, F., Cai, F., Shi, R., Wang, X. H. & Wu, X. T. Aging and age related stresses: a senescence mechanism of intervertebral disc degeneration. Osteoarthr. Cartil. 24, 398 (2016).   DOI
23 Kawamura, Y. et al. Sirt3 protects in vitro-fertilized mouse preimplantation embryos against oxidative stress-induced p53-mediated developmental arrest. J. Clin. Invest. 120, 2817 (2010).   DOI
24 Tseng, A. H., Shieh, S. S. & Wang, D. L. SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. Free Radic. Biol. Med. 63, 222 (2013).   DOI
25 Zhou, X. et al. Resveratrol regulates mitochondrial reactive oxygen species homeostasis through Sirt3 signaling pathway in human vascular endothelial cells. Cell Death Dis. 5, e1576 (2014).   DOI
26 Kim, H. S. et al. SIRT3 is a mitochondrial localized tumor suppressor required for maintenance of mitochondrial integrity and metabolism during stress. Cancer Cell. 17, 41 (2010).   DOI
27 Ballinger, S. W. et al. Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ. Res. 86, 960 (2000).   DOI
28 Sosulski, M. L., Gongora, R., Feghali-Bostwick, C., Lasky, J. A. & Sanchez, C. G. Sirtuin 3 deregulation promotes pulmonary fibrosis. J. Gerontol. A Biol. Sci. Med. Sci. 72, 595-602 (2017).
29 Zhou, Y. et al. Sirt3 deficiency increased the vulnerability of pancreatic beta cells to oxidative stress-induced dysfunction. Antioxid. Redox Signal. 27, 962-976 (2017).   DOI
30 Wei, T. et al. Sirtuin 3 deficiency accelerates hypertensive cardiac remodeling by impairing angiogenesis. J. Am. Heart Assoc. 6, e006114 (2017).
31 Sengupta, S. et al. Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3. Oncogene 36, 5709-5721 (2017).   DOI
32 Shen, J. et al. IL-1${\beta}$ induces apoptosis and autophagy via mitochondria pathway in human degenerative nucleus pulposus cells. Sci. Rep. 7, 41067 (2017).   DOI
33 Dagda, R. K., Kulich, S. M., Tandon, A., Park, D. & Chu, C. T. Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J. Biol. Chem. 284, 13843-13855 (2009).   DOI
34 Frank, M. et al. Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim. Biophys. Acta Mol. Cell Res. 1823, 2297-2310 (2012).   DOI