Abstract
Intervertebral disc (IVD) degeneration is a common finding on spine imaging that increases in prevalence with age. IVD degeneration is a frequent cause of low back pain, which is a leading cause of disability. The process of IVD degeneration consists of gradual structural change accompanied by severe alterations in metabolic homeostasis. IVD degeneration, like osteoarthritis, is a common comorbidity in patients with obesity and type 2 diabetes mellitus, two metabolic syndrome pathological conditions in which adipokines are important promoters of low-grade inflammation, extracellular matrix degradation and fibrosis. Impairment in white adipose tissue function, due to the abnormal fat accumulation in obesity, is characterized by increased production of specific pro-inflammatory proteins such as adipokines by white adipose tissue and of cytokines such as TNF by immune cells of the stromal compartment. Investigations into the immunometabolic alterations in obesity and type 2 diabetes mellitus and their interconnections with IVD degeneration provide insights into how adipokines might affect the pathogenesis of IVD degeneration and impair IVD function and repair. Toll-like receptor-mediated signalling has also been implicated as a promoter of the inflammatory response in the metabolic alterations associated with IVD and is thus thought to have a role in IVD degeneration. Pathological starvation, obesity and adipokine dysregulation can result in immunometabolic alterations, which could be targeted for the development of new therapeutics.
Key points
-
Intervertebral disc (IVD) degeneration is a common comorbidity in patients with obesity and those with type 2 diabetes mellitus.
-
Dysregulation of obesity-associated pro-inflammatory adipokines and high concentrations of circulating lipids promote a chronic state of low-grade inflammation and extracellular matrix degradation in the IVD.
-
Insulin resistance, hyperglycaemia, adipokines, advanced glycation end products and microvascular alterations negatively affect the IVD metabolic environment in type 2 diabetes mellitus.
-
Premature senescence, increased cellular apoptosis and altered autophagic mechanisms perpetuate a catabolic environment in the IVD.
-
Therapeutic strategies aimed at counteracting dysregulated pro-inflammatory adipokine production could be effective for the treatment of IVD degeneration.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
James, S. L. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789–1858 (2018).
Jin, Z. et al. Incidence trend of five common musculoskeletal disorders from 1990 to 2017 at the global, regional and national level: results from the global burden of disease study 2017. Ann. Rheum. Dis. 79, 1014–1022 (2020).
Ehrlich, G. E. Low back pain. Bull. World Health Organ. 81, 671–676 (2003).
Hartvigsen, J. et al. What low back pain is and why we need to pay attention. Lancet 391, 2356–2367 (2018).
Vlaeyen, J. W. S. et al. Low back pain. Nat. Rev. Dis. Prim. 4, 52 (2018).
Cheung, K. M. C. et al. Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals. Spine 34, 934–940 (2009).
Livshits, G. et al. 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. 70, 1740–1745 (2011).
Takatalo, J. et al. Does lumbar disc degeneration on magnetic resonance imaging associate with low back symptom severity in young Finnish adults? Spine 36, 2180–2189 (2011).
Brinjikji, W. et al. Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. Am. J. Neuroradiol. 36, 811–816 (2015).
Gallucci, M., Puglielli, E., Splendiani, A., Pistoia, F. & Spacca, G. Degenerative disorders of the spine. Eur. Radiol. 15, 591–598 (2005).
Kushchayev, S. V. et al. ABCs of the degenerative spine. Insights Imaging 9, 253–274 (2018).
Buckwalter, J. A. Aging and degeneration of the human intervertebral disc. Spine 20, 1307–1314 (1995).
Dudli, S. et al. ISSLS Prize in Basic Science 2017: intervertebral disc/bone marrow cross-talk with Modic changes. Eur. Spine J. 26, 1362–1373 (2017).
Dudli, S., Fields, A. J., Samartzis, D., Karppinen, J. & Lotz, J. C. Pathobiology of Modic changes. Eur. Spine J. 25, 3723–3734 (2016).
Anderson, D. G. & Tannoury, C. Molecular pathogenic factors in symptomatic disc degeneration. Spine J. 5, S260–S266 (2005).
Silagi, E. S. et al. The role of HIF proteins in maintaining the metabolic health of the intervertebral disc. Nat. Rev. Rheumatol. 17, 426–439 (2021).
Kadow, T., Sowa, G., Vo, N. & Kang, J. D. Molecular basis of intervertebral disc degeneration and herniations: what are the important translational questions? Clin. Orthop. Relat. Res. 473, 1903–1912 (2015).
Rajasekaran, S. et al. Human intervertebral discs harbour a unique microbiome and dysbiosis determines health and disease. Eur. Spine J. 29, 1621–1640 (2020).
Scanzello, C. R. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol. 29, 79–85 (2017).
Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).
Berenbaum, F. Osteoarthritis as an inflammatory disease (osteoarthritis is not osteoarthrosis!). Osteoarthritis Cartilage 21, 16–21 (2013).
Courties, A., Sellam, J. & Berenbaum, F. Metabolic syndrome-associated osteoarthritis. Curr. Opin. Rheumatol. 29, 214–222 (2017).
Courties, A. & Sellam, J. Osteoarthritis and type 2 diabetes mellitus: what are the links? Diabetes Res. Clin. Pract. 122, 198–206 (2016).
Francisco, V. et al. Adipokines: linking metabolic syndrome, the immune system, and arthritic diseases. Biochem. Pharmacol. 165, 196–206 (2019).
Sharma, A. The role of adipokines in intervertebral disc degeneration. Med. Sci. 6, 34 (2018).
Ruiz-Fernández, C. et al. Molecular relationships among obesity, inflammation and intervertebral disc degeneration: are adipokines the common link? Int. J. Mol. Sci. 20, 2030 (2019).
Rustenburg, C. M. E. et al. Osteoarthritis and intervertebral disc degeneration: quite different, quite similar. JOR Spine 1, e1033 (2018).
Czech, M. P. Insulin action and resistance in obesity and type 2 diabetes. Nat. Med. 11, 804–814 (2017).
Astrup, A. & Finer, N. Redefining type 2 diabetes: “diabesity” or “obesity dependent diabetes mellitus”? Obes. Rev. 1, 57–59 (2000).
Toplak, H. et al. “Diabesity” — obesity and type 2 diabetes (Update 2019). Wien. Klin. Wochenschr. 131, 71–76 (2019).
Aamir, K., Khan, H. U., Sethi, G., Hossain, M. A. & Arya, A. Wnt signaling mediates TLR pathway and promote unrestrained adipogenesis and metaflammation: therapeutic targets for obesity and type 2 diabetes. Pharmacol. Res. 152, 104602 (2020).
Samartzis, D., Karppinen, J., Chan, D., Luk, K. D. K. & Cheung, K. M. C. The association of lumbar intervertebral disc degeneration on magnetic resonance imaging with body mass index in overweight and obese adults: a population-based study. Arthritis Rheum. 64, 1488–1496 (2012).
Elgaeva, E. E. et al. ISSLS Prize in Clinical Science 2020. Examining causal effects of body mass index on back pain: a Mendelian randomization study. Eur. Spine J. 29, 686–691 (2020).
Grunhagen, T., Shirazi-Adl, A., Fairbank, J. C. T. & Urban, J. P. G. Intervertebral disk nutrition: a review of factors influencing concentrations of nutrients and metabolites. Orthop. Clin. North. Am. 42, 465–477 (2011).
Shi, J. et al. Increased lactic acid content associated with extracellular matrix depletion in a porcine disc degeneration induced by superficial annular lesion. BMC Musculoskelet. Disord. 20, 551 (2019).
Guehring, T. et al. Notochordal intervertebral disc cells: sensitivity to nutrient deprivation. Arthritis Rheum. 60, 1026–1034 (2009).
Zhao, Y. et al. Body mass index and polycystic ovary syndrome: a 2-sample bidirectional mendelian randomization study. J. Clin. Endocrinol. Metab. 105, dgaa125 (2020).
Urban, J. P. G. & Roberts, S. Degeneration of the intervertebral disc. Arthritis Res. Ther. 5, 120–130 (2003).
Yin, X. et al. Effects of glucose deprivation on ATP and proteoglycan production of intervertebral disc cells under hypoxia. Sci. Rep. 10, 8899 (2020).
Wills, C. R., Foata, B., González Ballester, M., Karppinen, J. & Noailly, J. Theoretical explorations generate new hypotheses about the role of the cartilage endplate in early intervertebral disk degeneration. Front. Physiol. 9, 1210 (2018).
Rade, M. et al. Vertebral endplate defect as initiating factor in intervertebral disc degeneration. Spine 43, 412–419 (2018).
Määttä, J. H. et al. Strong association between vertebral endplate defect and Modic change in the general population. Sci. Rep. 8, 16630 (2018).
Alpantaki, K., Kampouroglou, A., Koutserimpas, C., Effraimidis, G. & Hadjipavlou, A. Diabetes mellitus as a risk factor for intervertebral disc degeneration: a critical review. Eur. Spine J. 28, 2129–2144 (2019).
Cannata, F. et al. Osteoarthritis and type 2 diabetes: from pathogenetic factors to therapeutic intervention. Diabetes Metab. Res. Rev. 36, e3254 (2020).
Takatalo, J. et al. Association of abdominal obesity with lumbar disc degeneration — a magnetic resonance imaging study. PLoS One 8, e56244 (2013).
Lee, S. Y., Kim, W., Lee, S. U. & Choi, K. H. Relationship between obesity and lumbar spine degeneration: a cross-sectional study from the Fifth Korean National Health and Nutrition Examination Survey, 2010-2012. Metab. Syndr. Relat. Disord. 17, 60–66 (2019).
Xu, X., Li, X. & Wu, W. Association between overweight or obesity and lumbar disk diseases a meta-analysis. J. Spinal Disord. Tech. 28, 370–376 (2015).
Liuke, M. et al. Disc degeneration of the lumbar spine in relation to overweight. Int. J. Obes. 29, 903–908 (2005).
Chen, J. et al. Fat mass and obesity-associated (FTO) gene polymorphisms are associated with risk of intervertebral disc degeneration in Chinese Han population: a case control study. Med. Sci. Monit. 24, 5598–5609 (2018).
Wu, Z., Yang, Y. & Qiu, G. Association study between the polymorphisms of the fat mass- and obesity-associated gene with the risk of intervertebral disc degeneration in the Han Chinese population. Genet. Test. Mol. Biomark. 17, 756–762 (2013).
Dario, A. B. et al. The relationship between obesity, low back pain, and lumbar disc degeneration when genetics and the environment are considered: a systematic review of twin studies. Spine J. 15, 1106–1117 (2015).
Okada, E. et al. Aging of the cervical spine in healthy volunteers: a 10-year longitudinal magnetic resonance imaging study. Spine 34, 706–712 (2009).
Francisco, V. et al. Obesity, fat mass and immune system: role for leptin. Front. Physiol. 9, 640 (2018).
Scheja, L. & Heeren, J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat. Rev. Endocrinol. 15, 507–524 (2019).
Gruber, H. E., Ingram, J. A., Hoelscher, G. L. & Hanley, E. N. Leptin expression by annulus cells in the human intervertebral disc. Spine J. 7, 437–443 (2007).
Zhao, C. Q., Liu, D., Li, H., Jiang, L. S. & Dai, L. Y. Expression of leptin and its functional receptor on disc cells: contribution to cell proliferation. Spine 33, 858–864 (2008).
Li, Z. et al. Leptin induces cyclin d1 expression and proliferation of human nucleus pulposus cells via JAK/STAT, PI3K/Akt and MEK/ERK Pathways. PLoS One 7, e53176 (2012).
Koerner, J. D. et al. Differential gene expression in anterior and posterior annulus fibrosus. Spine 39, 1917–1923 (2014).
Li, Z. et al. The role of leptin on the organization and expression of cytoskeleton elements in nucleus pulposus cells. J. Orthop. Res. 31, 847–857 (2013).
Li, Z. et al. Leptin activates RhoA/ROCK pathway to induce cytoskeleton remodeling in nucleus pulposus cells. Int. J. Mol. Sci. 15, 1176–1188 (2014).
Segar, A. H., Fairbank, J. C. T. & Urban, J. Leptin and the intervertebral disc: a biochemical link exists between obesity, intervertebral disc degeneration and low back pain — an in vitro study in a bovine model. Eur. Spine J. 28, 214–223 (2019).
Miao, D. & Zhang, L. Leptin modulates the expression of catabolic genes in rat nucleus pulposus cells through the mitogen-activated protein kinase and Janus kinase 2/signal transducer and activator of transcription 3 pathways. Mol. Med. Rep. 12, 1761–1768 (2015).
Li, Z. et al. Leptin downregulates aggrecan through the p38-ADAMST pathway in human nucleus pulposus cells. PLoS One 9, e109595 (2014).
Han, Y. C. et al. Leptin regulates disc cartilage endplate degeneration and ossification through activation of the MAPK-ERK signalling pathway in vivo and in vitro. J. Cell. Mol. Med. 22, 2098–2109 (2018).
Ding, W. et al. Leptin induces terminal differentiation of rat annulus fibrosus cells via activation of MAPK signaling. Anat. Rec. 296, 1806–1812 (2013).
Sun, C., Wang, Z., Tian, J.-W. & Wang, Y.-H. Leptin-induced inflammation by activating IL-6 expression contributes to the fibrosis and hypertrophy of ligamentum flavum in lumbar spinal canal stenosis. Biosci. Rep. 38, 20171214 (2018).
Liu, M. & Liu, F. Regulation of adiponectin multimerization, signaling and function. Best. Pract. Res. Clin. Endocrinol. Metab. 28, 25–31 (2014).
Yuan, X. et al. The key role of canonical Wnt/β-catenin signaling in cartilage chondrocytes. Curr. Drug Targets 17, 475–484 (2015).
Rodríguez-Carrio, J. et al. Non-esterified fatty acids profiling in rheumatoid arthritis: associations with clinical features and Th1 response. PLoS One 11, e0159573 (2016).
Khabour, O. F., Abu-Rumeh, L., Al-Jarrah, M., Jamous, M. & Alhashimi, F. Association of adiponectin protein and ADIPOQ gene variants with lumbar disc degeneration. Exp. Ther. Med. 8, 1340–1344 (2014).
Yuan, B. et al. Adiponectin downregulates TNF-α expression in degenerated intervertebral discs. Spine 43, E381–E389 (2018).
Terashima, 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. 11, 1–9 (2016).
Steppan, C. M. et al. The hormone resistin links obesity to diabetes. Nature 409, 307–312 (2001).
Tarkowski, A., Bjersing, J., Shestakov, A. & Bokarewa, M. I. Resistin competes with lipopolysaccharide for binding to toll-like receptor 4. J. Cell. Mol. Med. 14, 1419–1431 (2010).
Francisco, V. et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: when the levee breaks. J. Orthop. Res. 36, 594–604 (2017).
Li, Z. et al. Resistin promotes CCL4 expression through toll-like receptor-4 and activation of the p38-MAPK and NF-κB signaling pathways: implications for intervertebral disc degeneration. Osteoarthritis Cartilage 25, 341–350 (2017).
Liu, C. et al. Resistin promotes intervertebral disc degeneration by upregulation of ADAMTS-5 through p38 MAPK signaling pathway. Spine 41, 1414–1420 (2016).
Shi, C. et al. Nicotinamide phosphoribosyltransferase inhibitor APO866 prevents IL-1β-induced human nucleus pulposus cell degeneration via autophagy. Cell. Physiol. Biochem. 49, 2463–2482 (2018).
Abella, V. et al. The potential of lipocalin-2/NGAL as biomarker for inflammatory and metabolic diseases. Biomarkers 20, 565–571 (2015).
Kao, T.-H. et al. Nerve growth factor increases MMP9 activity in annulus fibrosus cells by upregulating lipocalin 2 expression. Eur. Spine J. 24, 1959–1968 (2015).
Kao, T.-H., Peng, Y.-J., Tsou, H.-K., Salter, D. M. & Lee, H.-S. Nerve growth factor promotes expression of novel genes in intervertebral disc cells that regulate tissue degradation. J. Neurosurg. Spine 21, 653–661 (2014).
Francisco, V. et al. Adipokines and inflammation: is it a question of weight? Br. J. Pharmacol. 175, 1569–1579 (2018).
Liu, C. J. & Bosch, X. Progranulin: a growth factor, a novel TNFR ligand and a drug target. Pharmacol. Ther. 133, 124–132 (2012).
Wang, S. et al. Progranulin is positively associated with intervertebral disc degeneration by interaction with IL-10 and IL-17 through TNF pathways. Inflammation 41, 1852–1863 (2018).
Naphade, S. B. et al. Progranulin expression is upregulated after spinal contusion in mice. Acta Neuropathol. 119, 123–133 (2010).
Zhao, Y.-P. et al. Progranulin knockout accelerates intervertebral disc degeneration in aging mice. Sci. Rep. 5, 9102 (2015).
Ding, H. et al. Progranulin derived engineered protein Atsttrin suppresses TNF-a-mediated inflammation in intervertebral disc degenerative disease. Oncotarget 8, 109692–109702 (2017).
Lorenzi, T. et al. Ghrelin: a metabolic signal affecting the reproductive system. Cytokine Growth Factor. Rev. 20, 137–152 (2009).
Colldén, G., Tschöp, M. H. & Müller, T. D. Therapeutic potential of targeting the ghrelin pathway. Int. J. Mol. Sci. 18, 798 (2017).
Pereira, J. A. D. S., Silva, F. C. D. & De Moraes-Vieira, P. M. M. The impact of ghrelin in metabolic diseases: an immune perspective. J. Diabetes Res. 2017, 4527980 (2017).
Li, W. et al. Ghrelin protects against nucleus pulposus degeneration through inhibition of NF-κB signaling pathway and activation of Akt signaling pathway. Oncotarget 8, 91887–91901 (2017).
Teraguchi, M. et al. Progression, incidence, and risk factors for intervertebral disc degeneration in a longitudinal population-based cohort: the Wakayama Spine Study. Osteoarthritis Cartilage 25, 1122–1131 (2017).
Liu, X., Pan, F., Ba, Z., Wang, S. & Wu, D. The potential effect of type 2 diabetes mellitus on lumbar disc degeneration: a retrospective single-center study. J. Orthop. Surg. Res. 13, 52 (2018).
Fabiane, S. M., Ward, K. J., Iatridis, J. C. & Williams, F. M. K. Does type 2 diabetes mellitus promote intervertebral disc degeneration? Eur. Spine J. 25, 2716–2720 (2016).
Hangai, M. et al. Factors associated with lumbar intervertebral disc degeneration in the elderly. Spine J. 8, 732–740 (2008).
Videman, T. et al. Disc degeneration and bone density in monozygotic twins discordant for insulin-dependent diabetes mellitus. J. Orthop. Res. 18, 768–772 (2000).
Fields, A. J. et al. Alterations in intervertebral disc composition, matrix homeostasis and biomechanical behavior in the UCD-T2DM rat model of type 2 diabetes. J. Orthop. Res. 33, 738–746 (2015).
Huang, Y. C., Urban, J. P. G. & Luk, K. D. K. Intervertebral disc regeneration: do nutrients lead the way? Nat. Rev. Rheumatol. 10, 561–566 (2014).
Thrailkill, K. M. Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues. Am. J. Physiol. Endocrinol. Metab. 289, E735–E745 (2005).
Xu, H. M., Hu, F., Wang, X. Y. & Tong, S. L. Relationship between apoptosis of endplate microvasculature and degeneration of the intervertebral disk. World Neurosurg. 125, e392–e397 (2019).
Chen, S., Liao, M., Li, J., Peng, H. & Xiong, M. The correlation between microvessel pathological changes of the endplate and degeneration of the intervertebral disc in diabetic rats. Exp. Ther. Med. 5, 711–717 (2013).
Jiang, L. et al. Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: implications for diabetic intervertebral disc degeneration. J. Orthop. Res. 31, 692–702 (2013).
Liu, Y. et al. The effect of high glucose on the biological characteristics of nucleus pulposus-derived mesenchymal stem cells. Cell Biochem. Funct. 38, 130–140 (2020).
Jiang, Z. et al. High glucose-induced excessive reactive oxygen species promote apoptosis through mitochondrial damage in rat cartilage endplate cells. J. Orthop. Res. 36, 2476–2483 (2018).
Hou, G. et al. N-cadherin attenuates high glucose-induced nucleus pulposus cell senescence through regulation of the ROS/NF-κB pathway. Cell. Physiol. Biochem. 47, 257–265 (2018).
Kong, J. G., Park, J. B., Lee, D. & Park, E. Y. Effect of high glucose on stress-induced senescence of nucleus pulposus cells of adult rats. Asian Spine J. 9, 155–161 (2015).
Park, J.-B., Kong, J.-G., Lee, D. & Park, E.-Y. Stressed-induced senescence of adult rat nucleus pulposus cells effect of high glucose on stress-induced senescence of nucleus pulposus cells of adult rats. Asian Spine J. 9, 155–161 (2015).
Cheng, X., Ni, B., Zhang, F., Hu, Y. & Zhao, J. High glucose-induced oxidative stress mediates apoptosis and extracellular matrix metabolic imbalances possibly via p38 MAPK activation in rat nucleus pulposus cells. J. Diabetes Res. 2016, 3765173 (2016).
Svenja, I. J. et al. Chronic ingestion of advanced glycation end products induces degenerative spinal changes and hypertrophy in aging pre-diabetic mice. PLoS One 10, e0116625 (2015).
Li, X. et al. Intervertebral disc degeneration in mice with type II diabetes induced by leptin receptor deficiency. BMC Musculoskelet. Disord. 21, 77 (2020).
Natelson, D. M. et al. Leptin signaling and the intervertebral disc: sex dependent effects of leptin receptor deficiency and Western diet on the spine in a type 2 diabetes mouse model. PLoS One 15, e0227527 (2020).
Katsiki, N., Mikhailidis, D. P. & Banach, M. Leptin, cardiovascular diseases and type 2 diabetes mellitus. Acta Pharmacol. Sin. 39, 1176–1188 (2018).
Achari, A. E. & Jain, S. K. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int. J. Mol. Sci. 18, 1321 (2017).
Eckel, R. H. et al. Obesity and type 2 diabetes: what can be unified and what needs to be individualized? J. Clin. Endocrinol. Metab. 96, 1654–1663 (2011).
Jaganathan, R., Ravindran, R. & Dhanasekaran, S. Emerging role of adipocytokines in Type 2 diabetes as mediators of insulin resistance and cardiovascular disease. Can. J. Diabetes 42, 446–456.e1 (2018).
El Husseny, M. W. A. et al. Adipokines: potential therapeutic targets for vascular dysfunction in type II diabetes mellitus and obesity. J. Diabetes Res. 2017, 8095926 (2017).
Tang, G. et al. Latent infection of low-virulence anaerobic bacteria in degenerated lumbar intervertebral discs. BMC Musculoskelet. Disord. 19, 445 (2018).
Albert, H. B. et al. Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae? Eur. Spine J. 22, 690–696 (2013).
Fisher, T. J. & Osti, O. L. Do bacteria play an important role in the pathogenesis of low back pain? ANZ J. Surg. 85, 808–814 (2015).
Albert, H. B. Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur. Spine J. 22, 697–707 (2013).
Urquhart, D. M. et al. Could low grade bacterial infection contribute to low back pain? A systematic review. BMC Med. 13, 13 (2015).
Khalil, J. G., Gandhi, S. D., Park, D. K. & Fischgrund, J. S. Cutibacterium acnes in spine pathology: pathophysiology, diagnosis, and management. J. Am. Acad. Orthop. Surg. 27, e633–e640 (2019).
Bråten, L. C. H. et al. Efficacy of antibiotic treatment in patients with chronic low back pain and Modic changes (the AIM study): double blind, randomised, placebo controlled, multicentre trial. BMJ 367, l5654 (2019).
Gorth, D. J., Shapiro, I. M. & Risbud, M. V. Discovery of the drivers of inflammation induced chronic low back pain: from bacteria to diabetes. Discov. Med. 20, 177–184 (2015).
MV, R. & IM, S. Role of cytokines in intervertebral disc degeneration: pain and disc content. Nat. Rev. Rheumatol. 10, 44–56 (2014).
Krock, E. et al. Painful, degenerating intervertebral discs up-regulate neurite sprouting and CGRP through nociceptive factors. J. Cell. Mol. Med. 18, 1213–1225 (2014).
Alkhatib, B. et al. Acute mechanical injury of the human intervertebral disc: link to degeneration and pain. Eur. Cell Mater. 28, 98–111 (2014).
Binch, A. L. et al. Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration. Arthritis Res. Ther. 16, 416 (2014).
Gómez, R., Villalvilla, A., Largo, R., Gualillo, O. & Herrero-Beaumont, G. TLR4 signalling in osteoarthritis-finding targets for candidate DMOADs. Nat. Rev. Rheumatol. 11, 159–170 (2015).
Yu, L., Wang, L. & Chen, S. Endogenous toll-like receptor ligands and their biological significance. J. Cell. Mol. Med. 14, 2592–2603 (2010).
Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).
Mobasheri, A. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13, 302–311 (2017).
Schieker, M. et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med. 173, 509–515 (2020).
Tarkowski, A., Bokarewa, M., Nagaev, I., Dahlberg, L. & Smith, U. Proinflammatory properties resistin, an adipokine with potent. J. Immunol. Ref. 174, 5789–5795 (2005).
Franco-Trepat, E. et al. Visfatin connection: present and future in osteoarthritis and osteoporosis. J. Clin. Med. 8, 1178 (2019).
Wei, J., Hettinghouse, A. & Liu, C. The role of progranulin in arthritis. Ann. N. Y. Acad. Sci. 1383, 5–20 (2016).
Otero, M. et al. Chronic inflammation modulates ghrelin levels in humans and rats. Rheumatology 43, 306–310 (2004).
Francisco, V. et al. Levels of the novel endogenous antagonist of ghrelin receptor, liver-enriched antimicrobial peptide-2, in patients with rheumatoid arthritis. Nutrients 12, 1006 (2020).
Gerwick, L., Corley-Smith, G. & Bayne, C. J. Gene transcript changes in individual rainbow trout livers following an inflammatory stimulus. Fish. Shellfish. Immunol. 22, 157–171 (2007).
Escoté, X. et al. Role of omentin, vaspin, cardiotrophin-1, TWEAK and NOV/CCN3 in obesity and diabetes development. Int. J. Mol. Sci. 18, 1770 (2017).
Kuba, K., Sato, T., Imai, Y. & Yamaguchi, T. Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. Peptides 111, 62–70 (2019).
Helfer, G. & Wu, Q. F. Chemerin: a multifaceted adipokine involved in metabolic disorders. J. Endocrinol. 238, R79–R94 (2018).
Sakai, D. & Andersson, G. B. J. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nat. Rev. Rheumatol. 11, 243–256 (2015).
Acknowledgements
O.G. and F.L. are Staff Personnel (I3SNS Stable Researcher) of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff contract (Instituto de Salud Carlos III (ISCIII) /SERGAS). V.F. is a “Sara Borrell” Researcher funded by ISCIII and Fondo Europeo de Desarrollo Regional (FEDER) (CD16/00111) and Miguel Servet Programme (CP21/00025) funded by ISCIII. O.G. and M.A.G.G. are members of the RETICS Programme, RD16/0012/0014 (RIER: Red de Investigación en Inflamación y Enfermedades Reumáticas) and RICORS Programme, RD21/0002/0025 via ISCIII and FEDER. F.L. is a member of Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV). The work of O.G. and J.P. (PI17/00409 and PI20/00902), and F.L. (PI18/00821 and CB16/11/00226) is funded by ISCIII and FEDER. O.G. is a beneficiary of a project funded by the Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme (project number 734899). O.G. is the beneficiary of a grant funded by Xunta de Galicia, Consellería de Educación, Universidade e Formación Profesional and Consellería de Economía, Emprego e Industria (GAIN) (GPC IN607B2019/10). A.M. has received funding from the European Union’s Framework 7 programme (EU FP7; HEALTH.2012.2.4.5-2, project number 305815, the Innovative Medicines Initiative Joint Undertaking (grant agreement No. 115770, resources of which are composed of financial contribution from the EU FP7 (FP7/2007-2013) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contribution). A.M. acknowledges funding from the European Commission through a Marie Curie Intra-European Fellowship for Career Development grant (project number 625746; acronym: CHONDRION; FP7-PEOPLE-2013-IEF) and financial support from the European Structural and Social Funds (ES Struktūrinės Paramos) through the Research Council of Lithuania (Lietuvos Mokslo Taryba) according to the activity “Improvement of researchers’ qualification by implementing world-class R&D projects” of Measure No. 09.3.3-LMT-K-712 (grant application code: 09.3.3-LMT-K-712-01-0157, agreement No. DOTSUT-215) and the new funding programme “Attracting Foreign Researchers for Research Implementation (2018-2022)”.
Author information
Authors and Affiliations
Contributions
All authors researched data for the article, made substantial contributions to discussions of the content and contributed to writing, reviewing and/or editing the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Rheumatology thanks J. Lotz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Glossary
- Adipokines
-
Cytokines derived from adipose tissue that have pleiotropic functions in energy metabolism, immunity and inflammation; most adipokines are augmented in obesity and contribute to the associated low-grade inflammatory state.
- Adiposity
-
The quality or state of accumulating abnormal amounts of fat in the body, especially in the visceral compartment. Adiposity is associated with several secondary diseases, such as type 2 diabetes mellitus, hypertension, cardiovascular diseases, fatty liver and musculoskeletal diseases such as osteoarthritis and intervertebral disc degeneration.
- Notochordal cells
-
Cells of mesodermal origin that form the notochord, a rod-like structure that is the principal longitudinal structural element of chordates and of the early embryo of vertebrates.
- Bony endplate
-
A thin layer of porous bone, containing vessels, that is localized between the vertebral bone and cartilaginous endplate.
- Modic changes
-
Degenerative bone marrow changes seen in the vertebrae on MRI, with type 1 changes appearing as fibrovascular changes (mainly oedema and inflammation) in subchondral bone marrow, type 2 changes representing the conversion of yellow bone marrow to fat and type 3 changes appearing as highly mineralized, sclerotic bone.
- Spinal motion segments
-
Functional spinal units that represent the focus of biomechanical functioning of the spine, consisting of two adjacent vertebrae, the intervertebral disc and all adjoining ligaments.
- Cyclin D1
-
A protein that regulates cell-cycle progression through the G1 to S phase transition.
- Ligamentum flavum
-
One of a series of ligaments of yellow elastic tissue connecting the laminae of adjoining vertebrae from the axis to the sacrum, forming the posterior wall of the spinal canal.
- Metabolic syndrome
-
A condition characterized by three or more metabolic risk factors (including abdominal obesity, hypertension, dyslipidaemia and insulin resistance) and that is linked to an increased risk of the development of type 2 diabetes mellitus and cardiovascular disease.
Rights and permissions
About this article
Cite this article
Francisco, V., Pino, J., González-Gay, M.Á. et al. A new immunometabolic perspective of intervertebral disc degeneration. Nat Rev Rheumatol 18, 47–60 (2022). https://doi.org/10.1038/s41584-021-00713-z
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41584-021-00713-z
This article is cited by
-
Therapeutic effect and mechanism of Yougui Wan in rats with intervertebral disk degeneration
Journal of Orthopaedic Surgery and Research (2024)
-
Nucleus pulposus cells regulate macrophages in degenerated intervertebral discs via the integrated stress response-mediated CCL2/7-CCR2 signaling pathway
Experimental & Molecular Medicine (2024)
-
Pannexins in the musculoskeletal system: new targets for development and disease progression
Bone Research (2024)
-
Glutamine suppresses senescence and promotes autophagy through glycolysis inhibition-mediated AMPKα lactylation in intervertebral disc degeneration
Communications Biology (2024)
-
Mrgprb2-mediated mast cell activation exacerbates Modic changes by regulating immune niches
Experimental & Molecular Medicine (2024)