1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Andersson, G.B.J. Epidemiological features of chronic low-back pain. Lancet 1999, 354, 581–585. [CrossRef] [PubMed]
Martin, B.I.; Deyo, R.A.; Mirza, S.K.; Turner, J.A.; Comstock, B.A.; Hollingworth, W.; Sullivan, S.D. Expenditures and health status
among adults with back and neck problems. JAMA 2008, 299, 656–664. [CrossRef] [PubMed]
Livshits, G.; Popham, M.; Malkin, I.; Sambrook, P.N.; Macgregor, A.J.; Spector, T.; Williams, F.M.K. Lumbar disc degeneration
and genetic factors are the main risk factors for low back pain in women: The UK Twin Spine Study. Ann. Rheum. Dis. 2011, 70,
1740–1745. [CrossRef] [PubMed]
Urban, J.P.G.; Roberts, S. Degeneration of the intervertebral disc. Arthritis Res. Ther. 2003, 5, 120–130. [CrossRef]
Crock, H.V.; Goldwasser, M.; Yoshizawa, H. Vascular anatomy related to the intervertebral disc. In Biology of the Intervertebral Disc,
1st ed.; Ghosh, P., Ed.; CRC Press: Boca Raton, FL, USA, 1988; pp. 109–133.
Urban, J.P.G.; Smith, S.; Fairbank, J.C.T. Nutrition of the Intervertebral Disc. Spine 2004, 29, 2700–2709. [CrossRef]
Adams, M.A.; Roughley, P.J. What is intervertebral disc degeneration, and what causes it? Spine 2006, 31, 2151–2161. [CrossRef]
Shiri, R.; Karppinen, J.; Leino-Arjas, P.; Solovieva, S.; Viikari-Juntura, E. The association between obesity and low back pain: A
meta-analysis. Am. J. Epidemiol. 2010, 171, 135–154. [CrossRef]
Singla, P.; Bardoloi, A.; Parkash, A.A. Metabolic effects of obesity: A review. World J. Diabetes 2010, 1, 76–88. [CrossRef]
Risbud, M.V.; Shapiro, I.M. Role of cytokines in intervertebral disc degeneration: Pain and disc content. Nat. Rev. Rheumatol. 2014,
10, 44–56. [CrossRef]
Wang, S.Z.; Rui, Y.F.; Lu, J.; Wang, C. Cell and molecular biology of intervertebral disc degeneration: Current understanding and
implications for potential therapeutic strategies. Cell Prolif. 2014, 47, 381–390. [CrossRef]
Molinos, M.; Almeida, C.R.; Caldeira, J.; Cunha, C.; Goncalves, R.M.; Barbosa, M.A. Inflammation in intervertebral disc
degeneration and regeneration. J. R. Soc. Interface 2015, 12, 20141191. [CrossRef]
Tian, Y.; Yuan, W.; Fujita, N.; Wang, J.; Wang, H.; Shapiro, I.M.; Risbud, M.V. Inflammatory cytokines associated with degenerative
disc disease control aggrecanase-1 (ADAMTS-4) expression in nucleus pulposus cells through MAPK and NF-kappaB. Am. J.
Pathol. 2013, 182, 2310–2321. [CrossRef]
Int. J. Mol. Sci. 2023, 24, 8566
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
20 of 21
Miyazaki, K.; Miyazaki, S.; Yurube, T.; Takeoka, Y.; Kanda, Y.; Zhang, Z.; Kakiuchi, Y.; Tsujimoto, R.; Ohnishi, H.; Matsuo, T.; et al.
Protective effects of growth differentiation factor-6 on the intervertebral disc: An in vitro and in vivo study. Cells 2022, 11, 1174.
[CrossRef]
Wolf, A.M.; Wolf, D.; Rumpold, H.; Enrich, B.; Tilg, H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in
human leukocytes. Biochem. Biophys. Res. Commun. 2004, 323, 630–635. [CrossRef]
Fang, H.; Judd, R.L. Adiponectin regulation and function. Compr. Physiol. 2018, 8, 1031–1063.
Yamauchi, T.; Kamon, J.; Minokoshi, Y.; Ito, Y.; Waki, H.; Uchida, S.; Yamashita, S.; Noda, M.; Kita, S.; Ueki, K.; et al. Adiponectin
stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 2002, 8, 1288–1295.
[CrossRef]
Yamauchi, T.; Nio, Y.; Maki, T.; Kobayashi, M.; Takazawa, T.; Iwabu, M.; Okada-Iwabu, M.; Kawamoto, S.; Kubota, N.;
Kubota, T.; et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.
Nat. Med. 2007, 13, 332–339. [CrossRef]
Arita, Y.; Kihara, S.; Ouchi, N.; Takahashi, M.; Maeda, K.; Miyagawa, J.; Hotta, K.; Shimomura, I.; Nakamura, T.; Miyaoka, K.; et al.
Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem. Biophys. Res. Commun. 1999, 257, 79–83.
[CrossRef]
Chen, T.H.; Chen, L.; Hsieh, M.S.; Chang, C.P.; Chou, D.T.; Tsai, S.H. Evidence for a protective role for adiponectin in osteoarthritis.
Biochim. Biophys. Acta 2006, 1762, 711–718. [CrossRef]
Pattappa, G.; Li, Z.; Peroglio, M.; Wismer, N.; Alini, M.; Grad, S. Diversity of intervertebral disc cells: Phenotype and function.
J. Anat. 2012, 221, 480–496. [CrossRef]
Terashima, Y.; Kakutani, K.; Yurube, T.; Takada, T.; Maeno, K.; Hirata, H.; Miyazaki, S.; Ito, M.; Kakiuchi, Y.; Takeoka, Y.; et al.
Expression of adiponectin receptors in human and rat intervertebral disc cells and changes in receptor expression during disc
degeneration using a rat tail temporary static compression model. J. Orthop. Surg. Res. 2016, 11, 147. [CrossRef] [PubMed]
Yuan, B.; Huang, L.; Yan, M.; Zhang, S.; Zhang, Y.; Jin, B.; Ma, Y.; Luo, Z. Adiponectin downregulates TNF-alpha expression in
degenerated intervertebral discs. Spine 2018, 43, E381–E389. [CrossRef] [PubMed]
Wu, X.; Qiu, W.; Hu, Z.; Lian, J.; Liu, Y.; Zhu, X.; Tu, M.; Fang, F.; Yu, Y.; Valverde, P.; et al. An adiponectin receptor agonist
reduces type 2 diabetic periodontitis. J. Dent. Res. 2019, 98, 313–321. [CrossRef] [PubMed]
Okada-Iwabu, M.; Yamauchi, T.; Iwabu, M.; Honma, T.; Hamagami, K.; Matsuda, K.; Yamaguchi, M.; Tanabe, H.; KimuraSomeya, T.; Shirouzu, M.; et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 2013, 503,
493–499. [CrossRef]
Cheng, X.; Zhang, L.; Zhang, K.; Zhang, G.; Hu, Y.; Sun, X.; Zhao, C.; Li, H.; Li, Y.M.; Zhao, J. Circular RNA VMA21 protects
against intervertebral disc degeneration through targeting miR-200c and X linked inhibitor-of-apoptosis protein. Ann. Rheum.
Dis. 2018, 77, 770–779. [CrossRef]
Huang, Y.; Zhang, Z.; Wang, J.; Shen, S.; Yao, T.; Xu, Y.; Chen, Z.; Fang, B.; Ma, J. circSPG21 protects against intervertebral disc
disease by targeting miR-1197/ATP1B3. Exp. Mol. Med. 2021, 53, 1547–1558. [CrossRef]
Nunes, A.K.S.; Raposo, C.; Rocha, S.W.S.; de Sousa Barbosa, K.P.; de Almeida Luna, R.L. Involvement of AMPK, IKbetaalphaNFkappaB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model. Brain Res. 2015, 1627, 119–133.
[CrossRef]
Guma, M.; Wang, Y.; Viollet, B.; Liu-Bryan, R. AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis.
PLoS ONE 2015, 10, e0140452. [CrossRef]
Tang, S.N.; Walter, B.A.; Heimann, M.K.; Gantt, C.C.; Khan, S.N.; Kokiko-Cochran, O.N.; Askwith, C.C.; Purmessur, D. In vivo
mouse intervertebral disc degeneration models and their utility as translational models of clinical discogenic back pain: A
comparative review. Front. Pain Res. 2022, 3, 894651. [CrossRef]
Shi, C.; Das, V.; Li, X.; Kc, R.; Qiu, S.; O-Sullivan, I.; Ripper, R.L.; Kroin, J.S.; Mwale, F.; Wallace, A.A.; et al. Development of an
in vivo mouse model of discogenic low back pain. J. Cell Physiol. 2018, 233, 6589–6602. [CrossRef]
Colombini, A.; Lombardi, G.; Corsi, M.M.; Banfi, G. Pathophysiology of the human intervertebral disc. Int. J. Biochem. Cell Biol.
2008, 40, 837–842. [CrossRef]
Kepler, C.K.; Ponnappan, R.K.; Tannoury, C.A.; Risbud, M.V.; Anderson, D.G. The molecular basis of intervertebral disc
degeneration. Spine J. 2013, 13, 318–330. [CrossRef]
Ruffilli, A.; Viroli, G.; Neri, S.; Traversari, M.; Barile, F.; Manzetti, M.; Assirelli, E.; Ialuna, M.; Vita, F.; Faldini, C. Mechanobiology
of the Human Intervertebral Disc: Systematic Review of the Literature and Future Perspectives. Int. J. Mol. Sci. 2023, 24, 2728.
[CrossRef]
Wang, C.; Yu, X.; Yan, Y.; Yang, W.; Zhang, S.; Xiang, Y.; Zhang, J.; Wang, W. Tumor necrosis factor-alpha: A key contributor to
intervertebral disc degeneration. Acta Biochim. Biophys. Sin. 2017, 49, 1–13. [CrossRef]
Pan, H.; Li, H.; Guo, S.; Wang, C.; Long, L.; Wang, X.; Shi, H.; Zhang, K.; Chen, H.; Li, S. The mechanisms and functions of
TNF-alpha in intervertebral disc degeneration. Exp. Gerontol. 2023, 174, 112119. [CrossRef]
Tang, C.H.; Chiu, Y.C.; Tan, T.W.; Yang, R.S.; Fu, W.M. Adiponectin enhances IL-6 production in human synovial fibroblast via an
AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J. Immunol. 2007, 179, 5483–5492. [CrossRef]
Int. J. Mol. Sci. 2023, 24, 8566
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
21 of 21
Lee, Y.A.; Ji, H.I.; Lee, S.H.; Hong, S.J.; Yang, H.I.; Yoo, M.C.; Kim, K.S. The role of adiponectin in the production of IL-6, IL-8,
VEGF and MMPs in human endothelial cells and osteoblasts: Implications for arthritic joints. Exp. Mol. Med. 2014, 46, e72.
[CrossRef]
Wong, H.L.; Wang, M.X.; Cheung, P.T.; Yao, K.M.; Chan, B.P. A 3D collagen microsphere culture system for GDNF-secreting
HEK293 cells with enhanced protein productivity. Biomaterials 2007, 28, 5369–5380. [CrossRef]
Yukawa, H.; Ikeuchi, M.; Noguchi, H.; Miyamoto, Y.; Ikuta, K.; Hayashi, S. Embryonic body formation using the tapered soft
stencil for cluster culture device. Biomaterials 2011, 32, 3729–3738. [CrossRef]
Vo, N.V.; Hartman, R.A.; Yurube, T.; Jacobs, L.J.; Sowa, G.A.; Kang, J.D. Expression and regulation of metalloproteinases and their
inhibitors in intervertebral disc aging and degeneration. Spine J. 2013, 13, 331–341. [CrossRef]
Millward-Sadler, S.J.; Costello, P.W.; Freemont, A.J.; Hoyland, J.A. Regulation of catabolic gene expression in normal and
degenerate human intervertebral disc cells: Implications for the pathogenesis of intervertebral disc degeneration. Arthritis Res.
Ther. 2009, 11, R65. [CrossRef] [PubMed]
Wang, J.; Markova, D.; Anderson, D.G.; Zheng, Z.; Shapiro, I.M.; Risbud, M.V. TNF-alpha and IL-1beta promote a disintegrin-like
and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral
disc. J. Biol. Chem. 2011, 286, 39738–39749. [CrossRef] [PubMed]
Scotece, M.; Perez, T.; Conde, J.; Abella, V.; Lopez, V.; Pino, J.; Gonzalez-Gay, M.A.; Gomez-Reino, J.J.; Mera, A.; Gomez, R.; et al.
Adipokines induce pro-inflammatory factors in activated Cd4+ T cells from osteoarthritis patient. J. Orthop. Res. 2017, 35,
1299–1303. [CrossRef] [PubMed]
Napetschnig, J.; Wu, H. Molecular basis of NF-kappaB signaling. Annu. Rev. Biophys. 2013, 42, 443–468. [CrossRef]
Salminen, A.; Hyttinen, J.M.; Kaarniranta, K. AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation:
Impact on healthspan and lifespan. J. Mol. Med. 2011, 89, 667–676. [CrossRef]
Nasto, L.A.; Seo, H.Y.; Robinson, A.R.; Tilstra, J.S.; Clauson, C.L.; Sowa, G.A.; Ngo, K.; Dong, Q.; Pola, E.; Lee, J.Y.; et al. ISSLS
prize winner: Inhibition of NF-kappaB activity ameliorates age-associated disc degeneration in a mouse model of accelerated
aging. Spine 2012, 37, 1819–1825. [CrossRef]
Pfirrmann, C.W.; Metzdorf, A.; Zanetti, M.; Hodler, J.; Boos, N. Magnetic resonance classification of lumbar intervertebral disc
degeneration. Spine 2001, 26, 1873–1878. [CrossRef]
Yurube, T.; Takada, T.; Hirata, H.; Kakutani, K.; Maeno, K.; Zhang, Z.; Yamamoto, J.; Doita, M.; Kurosaka, M.; Nishida, K.
Modified house-keeping gene expression in a rat tail compression loading-induced disc degeneration model. J. Orthop. Res. 2011,
29, 1284–1290. [CrossRef]
Jimbo, K.; Park, J.S.; Yokosuka, K.; Sato, K.; Nagata, K. Positive feedback loop of interleukin-1β upregulating production of
inflammatory mediators in human intervertebral disc cells in vitro. J. Neurosurg. Spine 2005, 2, 589–595. [CrossRef]
Wang, L.; Gu, Y.; Zhao, H.; Chen, R.; Chen, W.; Qi, H.; Gao, W. Dioscin Attenuates Interleukin 1beta (IL-1beta)-Induced Catabolism
and Apoptosis via Modulating the Toll-Like Receptor 4 (TLR4)/Nuclear Factor kappa B (NF-kappaB) Signaling in Human
Nucleus Pulposus Cells. Med. Sci. Monit. 2020, 26, e923386. [CrossRef]
Kameyama, K.; Motoyama, K.; Tanaka, N.; Yamashita, Y.; Higashi, T.; Arima, H. Induction of mitophagy-mediated antitumor
activity with folate-appended methyl-beta-cyclodextrin. Int. J. Nanomed. 2017, 12, 3433–3446. [CrossRef]
Han, B.; Zhu, K.; Li, F.-C.; Xiao, Y.-X.; Feng, J.; Shi, Z.-L.; Lin, M.; Wang, J.; Chen, Q.-X. A simple disc degeneration model induced
by percutaneous needle puncture in the rat tail. Spine 2008, 33, 1925–1934. [CrossRef]
Masuda, K.; Aota, Y.; Muehleman, C.; Imai, Y.; Okuma, M.; Thonar, E.J.; Andersson, G.B.; An, H.S. A novel rabbit model of mild,
reproducible disc degeneration by an anulus needle puncture: Correlation between the degree of disc injury and radiological and
histological appearances of disc degeneration. Spine 2005, 30, 5–14. [CrossRef]
Nishida, K.; Doita, M.; Takada, T.; Kakutani, K.; Miyamoto, H.; Shimomura, T.; Maeno, K.; Kurosaka, M. Sustained transgene
expression in intervertebral disc cells in vivo mediated by microbubble-enhanced ultrasound gene therapy. Spine 2006, 31,
1415–1419. [CrossRef]
Suzuki, T.; Nishida, K.; Kakutani, K.; Maeno, K.; Yurube, T.; Takada, T.; Kurosaka, M.; Doita, M. Sustained long-term RNA
interference in nucleus pulposus cells in vivo mediated by unmodified small interfering RNA. Eur. Spine J. 2009, 18, 263–270.
[CrossRef]
Duan, Z.X.; Tu, C.; Liu, Q.; Li, S.Q.; Li, Y.H.; Xie, P.; Li, Z.H. Adiponectin receptor agonist AdipoRon attenuates calcification of
osteoarthritis chondrocytes by promoting autophagy. J. Cell Biochem. 2020, 121, 3333–3344. [CrossRef]
Shinohara, I.; Kataoka, T.; Mifune, Y.; Inui, A.; Sakata, R.; Nishimoto, H.; Yamaura, K.; Mukohara, S.; Yoshikawa, T.; Kato, T.; et al.
Influence of adiponectin and inflammatory cytokines in fatty degenerative atrophic muscle. Sci. Rep. 2022, 12, 1557. [CrossRef]
Lai, A.; Gansau, J.; Gullbrand, S.E.; Crowley, J.; Cunha, C.; Dudli, S.; Engiles, J.B.; Fusellier, M.; Goncalves, R.M.;
Nakashima, D.; et al. Development of a standardized histopathology scoring system for intervertebral disc degeneration in rat
models: An initiative of the ORS spine section. JOR Spine 2021, 4, e1150. [CrossRef]
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