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A new immunometabolic perspective of intervertebral disc degeneration

Nature Reviews Rheumatology volume 18, pages 47–60 (2022)Cite this article

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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.

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Fig. 1: Diabesity, low-grade inflammation and IVD degeneration.
Fig. 2: Adipokines involved in low-grade inflammation and metabolic responses in IVD degeneration.

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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)”.

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Author notes

  1. These authors contributed equally: Vera Francisco, Jesús Pino.

Authors and Affiliations

  1. The NEIRID group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), C027-Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain

    Vera Francisco, Jesús Pino & Oreste Gualillo

  2. Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Universidad de Cantabria and IDIVAL, Hospital Universitario Marqués de Valdecilla, Santander, Spain

    Miguel Ángel González-Gay

  3. Molecular and Cellular Cardiology Group, SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), Research Laboratory 7, Santiago University Clinical Hospital, Santiago de Compostela, Spain

    Francisca Lago

  4. Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland

    Jaro Karppinen

  5. Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland

    Osmo Tervonen & Ali Mobasheri

  6. Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania

    Ali Mobasheri

  7. University Medical Center Utrecht, Departments of Orthopedics, Rheumatology and Clinical Immunology, Utrecht, The Netherlands

    Ali Mobasheri

  8. World Health Organization Collaborating Center for Public Health Aspects of Musculoskeletal Health and Aging, Université de Liège, Liège, Belgium

    Ali Mobasheri

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  1. Vera Francisco
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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.

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Correspondence to Oreste Gualillo.

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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.

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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

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