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Review| Volume 23, ISSUE 7, P1057-1070, July 2015

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Mechanics and biology in intervertebral disc degeneration: a vicious circle

Open ArchivePublished:March 27, 2015DOI:https://doi.org/10.1016/j.joca.2015.03.028

      Summary

      Intervertebral disc degeneration is a major cause of low back pain. Despite its long history and large socio-economical impact in western societies, the initiation and progress of disc degeneration is not well understood and a generic disease model is lacking. In literature, mechanics and biology have both been implicated as the predominant inductive cause; here we argue that they are interconnected and amplify each other. This view is supported by the growing awareness that cellular physiology is strongly affected by mechanical loading. We propose a vicious circle of mechanical overloading, catabolic cell response, and degeneration of the water-binding extracellular matrix. Rather than simplifying the disease, the model illustrates the complexity of disc degeneration, because all factors are interrelated. It may however solve some of the controversy in the field, because the vicious circle can be entered at any point, eventually leading to the same pathology. The proposed disease model explains the comparable efficacy of very different animal models of disc degeneration, but also helps to consider the consequences of therapeutic interventions, either at the cellular, material or mechanical level.

      Keywords

      Introduction

      Low back pain is a top-3 cause of disability in developed countries, and the number of people affected is increasing worldwide
      • Murray C.J.L.
      • Vos T.
      • Lozano R.
      • Naghavi M.
      • Flaxman A.D.
      • Michaud C.
      • et al.
      Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
      . Up to 40% of adult persons in the United States report low back pain in the preceding 3 months, and with 20–33% of patients being unable to work, the disease has a major socio-economic impact
      Spine: low back and neck pain.
      • Lambeek L.C.
      • van Tulder M.W.
      • Swinkels I.C.S.
      • Koppes L.L.J.
      • Anema J.R.
      • van Mechelen W.
      The trend in total cost of back pain in The Netherlands in the period 2002 to 2007.
      . In the Netherlands, recent policy changes in the management of low back pain have decreased expenditure, but the total costs are still 216 euro's per capita annually
      • Lambeek L.C.
      • van Tulder M.W.
      • Swinkels I.C.S.
      • Koppes L.L.J.
      • Anema J.R.
      • van Mechelen W.
      The trend in total cost of back pain in The Netherlands in the period 2002 to 2007.
      . Prevention and therapeutic intervention is hampered because the veritable cause of low back pain remains unclear; however, a correlation with intervertebral disc degeneration has been documented
      Spine: low back and neck pain.
      • Cheung K.M.C.
      • Karppinen J.
      • Chan D.
      • Ho D.W.H.
      • Song Y.-Q.
      • Sham P.
      • et al.
      Prevalence and pattern of lumbar magnetic resonance imaging changes in a population study of one thousand forty-three individuals.
      • Wang Y.
      • Videman T.
      • Battié M.C.
      ISSLS prize winner: lumbar vertebral endplate lesions: associations with disc degeneration and back pain history.
      • Teraguchi M.
      • Yoshimura N.
      • Hashizume H.
      • Muraki S.
      • Yamada H.
      • Minamide A.
      • et al.
      Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study.
      • Luoma K.
      • Riihimäki H.
      • Luukkonen R.
      • Raininko R.
      • Viikari-Juntura E.
      • Lamminen A.
      Low back pain in relation to lumbar disc degeneration.
      • Scheele J.
      • De Schepper E.I.T.
      • Van Meurs J.B.J.
      • Hofman A.
      • Koes B.W.
      • Luijsterburg P.A.J.
      • et al.
      Association between spinal morning stiffness and lumbar disc degeneration: the Rotterdam Study.
      • de Schepper E.I.T.
      • Damen J.
      • van Meurs J.B.J.
      • Ginai A.Z.
      • Popham M.
      • Hofman A.
      • et al.
      The association between lumbar disc degeneration and low back pain: the influence of age, gender, and individual radiographic features.
      • Livshits G.
      • Popham M.
      • Malkin I.
      • Sambrook P.N.
      • Macgregor A.J.
      • Spector T.
      • et al.
      Lumbar disc degeneration and genetic factors are the main risk factors for low back pain in women: the UK Twin Spine Study.
      . Unfortunately, the aetiology of intervertebral disc degeneration is as obscure as the cause of low back pain, and the current consensus is that it is “multi-factorial”. Numerous changes in disc morphology and physiology have been described, but these alterations have not yet lead to a widely accepted disease model. The lack of an accepted explanatory model limits the understanding of this disabling disease, and hampers the development of effective therapies.
      One of the issues to be resolved is the order and causal relationship of the biological and biomechanical alterations that occur in intervertebral disc degeneration. Some authors hypothesize that disc degeneration originates from biomechanical wear and tear
      • Adams M.A.
      • Dolan P.
      • McNally D.S.
      The internal mechanical functioning of intervertebral discs and articular cartilage, and its relevance to matrix biology.
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Adams M.A.
      • Lama P.
      • Zehra U.
      • Dolan P.
      Why do some intervertebral discs degenerate, when others (in the same spine) do not?.
      . Other authors focus on the disturbance of physiological cellular behaviour, mainly based on a loss of nutrition
      • Boubriak O.A.
      • Watson N.
      • Sivan S.S.
      • Stubbens N.
      • Urban J.P.G.
      Factors regulating viable cell density in the intervertebral disc: blood supply in relation to disc height.
      • Urban J.P.G.
      • Roberts S.
      Degeneration of the intervertebral disc.
      • Urban J.P.G.
      • Smith S.
      • Fairbank J.C.T.
      Nutrition of the intervertebral disc.
      • Urban J.P.G.
      The role of the physicochemical environment in determining disc cell behaviour.
      , but recently pathogens have been implicated as well
      • Alpantaki K.
      • Katonis P.
      • Hadjipavlou A.G.
      • Spandidos D.A.
      • Sourvinos G.
      Herpes virus infection can cause intervertebral disc degeneration: a causal relationship?.
      . However, these two viewpoints do not exclude each other, and it is conceivable that different pathological processes cause the same disease, equivalent to the etiological disease model of diabetes mellitus with subtypes 1 and 2. In fact, the dichotomy between biology and mechanics currently seen in the field may be unnecessary, as it has long been recognized that cellular physiology is affected by its mechanical environment
      • Hueter C.
      Anatomische Studien an den Extremitätengelenken Neugeborener und Erwachsener.
      • Volkmann R.
      Chirurgische Erfahrungen über Knochenverbiegungen und Knochenwachsthum.
      . This relationship, known as mechanobiology
      • van der Meulen M.C.H.
      • Huiskes R.
      Why mechanobiology? A survey article..
      , has recently also been established for the intervertebral disc
      • Paul C.P.L.
      • Zuiderbaan H.A.
      • Zandieh Doulabi B.
      • van der Veen A.J.
      • van de Ven P.M.
      • Smit T.H.
      • et al.
      Simulated-physiological loading conditions preserve biological and mechanical properties of caprine lumbar intervertebral discs in ex vivo culture.
      • Paul C.P.L.
      • Schoorl T.
      • Zuiderbaan H.A.
      • Zandieh Doulabi B.
      • van der Veen A.J.
      • van de Ven P.M.
      • et al.
      Dynamic and static overloading induce early degenerative processes in caprine lumbar intervertebral discs.
      • Gawri R.
      • Moir J.
      • Ouellet J.
      • Beckman L.
      • Steffen T.
      • Roughley P.
      • et al.
      Physiological loading can restore the proteoglycan content in a model of early IVD degeneration.
      , and is deemed instrumental in developing intervertebral disc degeneration
      • Hsieh A.H.
      • Twomey J.D.
      Cellular mechanobiology of the intervertebral disc: new directions and approaches.
      • Wuertz K.
      • Godburn K.
      • MacLean J.J.
      • Barbir A.
      • Stinnet Donnelly J.
      • Roughley P.J.
      • et al.
      In vivo remodeling of intervertebral discs in response to short- and long-term dynamic compression.
      • Setton L.A.
      • Chen J.
      Cell mechanics and mechanobiology in the intervertebral disc.
      • Chan S.C.W.
      • Ferguson S.J.
      • Gantenbein-Ritter B.
      The effects of dynamic loading on the intervertebral disc.
      • Lotz J.C.
      • Staples A.
      • Walsh A.
      • Hsieh A.H.
      Mechanobiology in intervertebral disc degeneration and regeneration.
      .
      Similar to developing wrinkles in the skin, degeneration of the intervertebral disc is part of normal aging. In analogy to this, the painful degenerative disc disease
      • Adams M.A.
      • Roughley P.J.
      What is intervertebral disc degeneration, and what causes it?.
      has been likened to accelerated aging of the disc
      • Adams M.A.
      • Dolan P.
      Intervertebral disc degeneration: evidence for two distinct phenotypes.
      . As such, it is important to realize similar processes occur in aging and degeneration alike, and a clear discrimination between the two is difficult. Additionally, there is a strong genetic basis for intervertebral disc degeneration
      • Battié M.C.
      • Videman T.
      • Kaprio J.
      • Gibbons L.E.
      • Gill K.
      • Manninen H.
      • et al.
      The Twin Spine Study: contributions to a changing view of disc degeneration.
      • Battié M.C.
      • Videman T.
      Lumbar disc degeneration: epidemiology and genetics.
      , because genetic information determines cellular behaviour and structural integrity of produced extracellular matrix. Therefore, polymorphisms in genes such as COLIA1 and or ADAMTS5 are a risk factor for developing degeneration at a younger age
      • Rajasekaran S.
      • Kanna R.M.
      • Senthil N.
      • Raveendran M.
      • Cheung K.M.C.
      • Chan D.
      • et al.
      Phenotype variations affect genetic association studies of degenerative disc disease: conclusions of analysis of genetic association of 58 single nucleotide polymorphisms with highly specific phenotypes for disc degeneration in 332 subjects.
      • Kepler C.K.
      • Ponnappan R.K.
      • Tannoury C.A.
      • Risbud M.V.
      • Anderson D.G.
      The molecular basis of intervertebral disc degeneration.
      . Nevertheless, neither age nor genetic make-up can be remedied; therefore, it is more relevant to look at what underlying processes are involved in order to halt or reverse intervertebral disc degeneration.
      In this paper, we present a contemporary disease model of intervertebral disc degeneration. While this model can not explain low back pain, the development of a disease model is essential in identifying lapses in knowledge and development of therapies for associated intervertebral disc degeneration. Our disease model is based on the changes that occur in the nucleus pulposus, and is in the form of a positive feedback loop involving cells, extracellular matrix, and biomechanics (Fig. 1). Novel in this model are the mechanobiological cues that close the loop from biomechanics to cells, and involve a shift from hydrostatic stress to shear stress in the nucleus pulposus. In order to demonstrate that most common risk factors for developing intervertebral disc degeneration can initiate the positive feedback loop, we additionally apply the interactions in this model to human epidemiology, and observations in the different animal models for disc degeneration. The deliberation of the model will be preceded by a short introduction to the functional anatomy of the intervertebral disc and the changes of structures with degeneration.
      Figure thumbnail gr1
      Fig. 1Concept of the degenerative circle of intervertebral disc degeneration.

      The intervertebral disc and its anatomical structures in health and degeneration

      Intervertebral discs are embedded between the vertebrae and provide flexibility to the spine. They consist of three anatomical parts: the nucleus pulposus, the annulus fibrosus, and the cartilaginous endplates. The nucleus is the core of the intervertebral disc, and is surrounded by the lamellae of the annulus fibrosus. Cranially and caudally the endplates limit the intervertebral disc, and form the anchoring into the vertebral bodies. Discus degeneration is associated with changes in all these anatomical structures. These alterations have been extensively reviewed in numerous papers
      • Urban J.P.G.
      • Roberts S.
      Degeneration of the intervertebral disc.
      • Adams M.A.
      • Roughley P.J.
      What is intervertebral disc degeneration, and what causes it?.
      • Kepler C.K.
      • Ponnappan R.K.
      • Tannoury C.A.
      • Risbud M.V.
      • Anderson D.G.
      The molecular basis of intervertebral disc degeneration.
      • Weiler C.
      • Nerlich A.G.
      • Zipperer J.
      • Bachmeier B.E.
      • Boos N.
      2002 SSE Award Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption.
      • Boos N.
      • Weissbach S.
      • Rohrbach H.
      • Weiler C.
      • Spratt K.F.
      • Nerlich A.G.
      Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science.
      • Zhao C.-Q.
      • Wang L.-M.
      • Jiang L.-S.
      • Dai L.-Y.
      The cell biology of intervertebral disc aging and degeneration.
      • Hadjipavlou A.G.
      • Tzermiadianos M.N.
      • Bogduk N.
      • Zindrick M.R.
      The pathophysiology of disc degeneration: a critical review.
      • Hsieh A.H.
      • Yoon S.T.
      Update on the pathophysiology of degenerative disc disease and new developments in treatment strategies.
      • Inoue N.
      • Espinoza Orías A.A.
      Biomechanics of intervertebral disk degeneration.
      • Antoniou J.
      • Steffen T.
      • Nelson F.
      • Winterbottom N.
      • Hollander A.P.
      • Poole R.A.
      • et al.
      The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.
      , hence only short summary of the nucleus', annulus' and endplates' structure in a normal and a degenerated intervertebral disc will be provided.
      A healthy nucleus pulposus is a gel-like, highly hydrated tissue, rich in proteoglycans
      • Roughley P.J.
      • Melching L.I.
      • Heathfield T.F.
      • Pearce R.H.
      • Mort J.S.
      The structure and degradation of aggrecan in human intervertebral disc.
      . The healthy nucleus pulposus generates an intradiscal pressure which separates the two vertebrae, tensions the annulus fibrosus, and distributes pressure evenly over the two adjacent endplates
      • Inoue N.
      • Espinoza Orías A.A.
      Biomechanics of intervertebral disk degeneration.
      • Iatridis J.C.
      • Nicoll S.B.
      • Michalek A.J.
      • Walter B.A.
      • Gupta M.S.
      Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?.
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      • Vergroesen P.-P.A.
      • van der Veen A.J.
      • van Royen B.J.
      • Kingma I.
      • Smit T.H.
      Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.
      . A degenerated nucleus pulposus is an unorganized fibrous tissue which has largely lost its capacity to bind water under compression
      • Roughley P.J.
      • Melching L.I.
      • Heathfield T.F.
      • Pearce R.H.
      • Mort J.S.
      The structure and degradation of aggrecan in human intervertebral disc.
      . Therefore, the pressure in the nucleus pulposus is dwindling
      • Sato K.
      • Kikuchi S.
      • Yonezawa T.
      In vivo intradiscal pressure measurement in healthy individuals and in patients with ongoing back problems.
      , and disc height is lost
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      • Vergroesen P.-P.A.
      • van der Veen A.J.
      • van Royen B.J.
      • Kingma I.
      • Smit T.H.
      Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.
      . Overall, the nucleus undergoes the highest degree of remodelling during intervertebral disc degeneration
      • Iatridis J.C.
      • Nicoll S.B.
      • Michalek A.J.
      • Walter B.A.
      • Gupta M.S.
      Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?.
      • Weiler C.
      • Schietzsch M.
      • Kirchner T.
      • Nerlich A.G.
      • Boos N.
      • Wuertz K.
      Age-related changes in human cervical, thoracal and lumbar intervertebral disc exhibit a strong intra-individual correlation.
      .
      A healthy annulus fibrosus is a highly organized fibrous structure. It consists of ∼20 concentric lamellae of alternating oblique collagen fibres interspersed with proteoglycans
      • Marchand F.
      • Ahmed A.M.
      Investigation of the laminate structure of lumbar disc anulus fibrosus.
      • Skaggs D.L.
      • Weidenbaum M.
      • Iatridis J.C.
      • Ratcliffe A.
      • Mow V.C.
      Regional variation in tensile properties and biochemical composition of the human lumbar anulus fibrosus.
      . The collagen fibres are tensioned by intradiscal pressure through two mechanisms: direct radial pressure from the nucleus pulposus, and cranial-caudal stretch from the separation of the two endplates
      • Inoue N.
      • Espinoza Orías A.A.
      Biomechanics of intervertebral disk degeneration.
      • Iatridis J.C.
      • Nicoll S.B.
      • Michalek A.J.
      • Walter B.A.
      • Gupta M.S.
      Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?.
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      . Due to a loss of intradiscal pressure, the annulus fibrosus of a degenerated intervertebral disc deforms by in- and out-ward bulging and buckling
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      • Thompson J.P.
      • Pearce R.H.
      • Schechter M.T.
      • Adams M.E.
      • Tsang I.K.
      • Bishop P.B.
      Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc.
      • Stefanakis M.
      • Luo J.
      • Pollintine P.
      • Dolan P.
      • Adams M.A.
      ISSLS prize winner: mechanical influences in progressive intervertebral disc degeneration.
      , and shows progressive increase of structural defects such as: rim lesions, de-lamination and radial fissures
      • Adams M.A.
      • Roughley P.J.
      What is intervertebral disc degeneration, and what causes it?.
      • Inoue N.
      • Espinoza Orías A.A.
      Biomechanics of intervertebral disk degeneration.
      • Marchand F.
      • Ahmed A.M.
      Investigation of the laminate structure of lumbar disc anulus fibrosus.
      . Remarkably, despite these structural changes, there is hardly any loss of tensile strength
      • Holzapfel G.A.
      • Schulze-Bauer C.A.J.
      • Feigl G.
      • Regitnig P.
      Single lamellar mechanics of the human lumbar anulus fibrosus.
      • Ebara S.
      • Iatridis J.C.
      • Setton L.A.
      • Foster R.J.
      • Mow V.C.
      • Weidenbaum M.
      Tensile properties of nondegenerate human lumbar anulus fibrosus.
      ; however, hydraulic permeability changes from anisotropy favouring the radial direction to isotropy
      • Gu W.Y.
      • Mao X.G.
      • Foster R.J.
      • Weidenbaum M.
      • Mow V.C.
      • Rawlins B.A.
      The anisotropic hydraulic permeability of human lumbar anulus fibrosus. Influence of age, degeneration, direction, and water content.
      • Iatridis J.C.
      • Setton L.A.
      • Foster R.J.
      • Rawlins B.A.
      • Weidenbaum M.
      • Mow V.C.
      Degeneration affects the anisotropic and nonlinear behaviors of human anulus fibrosus in compression.
      , which could affect the build-up of intradiscal pressure.
      Healthy vertebral endplates are of uniform thickness, do not bulge into the vertebrae and appear as homogeneous hyaline cartilage
      • Thompson J.P.
      • Pearce R.H.
      • Schechter M.T.
      • Adams M.E.
      • Tsang I.K.
      • Bishop P.B.
      Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc.
      • Rutges J.P.H.J.
      • Duit R.A.
      • Kummer J.A.
      • Bekkers J.E.J.
      • Oner F.C.
      • Castelein R.M.
      • et al.
      A validated new histological classification for intervertebral disc degeneration.
      . With intervertebral disc degeneration, there is an increase in microscopic and macroscopic damage to the endplate
      • Boos N.
      • Weissbach S.
      • Rohrbach H.
      • Weiler C.
      • Spratt K.F.
      • Nerlich A.G.
      Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science.
      • Wang Y.
      • Videman T.
      • Battié M.C.
      Lumbar vertebral endplate lesions: prevalence, classification, and association with age.
      . Additionally, there is a marked increase in sclerosis of the subchondral bone
      • Katz M.E.
      • Teitelbaum S.L.
      • Gilula L.A.
      • Resnick D.
      • Katz S.J.
      Radiologic and pathologic patterns of end-plate-based vertebral sclerosis.
      • Benneker L.M.
      • Heini P.F.
      • Alini M.
      • Anderson S.E.
      • Ito K.
      2004 Young Investigator Award Winner: vertebral endplate marrow contact channel occlusions and intervertebral disc degeneration.
      • Rutges J.P.H.J.
      • Jagt van der O.P.
      • Oner F.C.
      • Verbout A.J.
      • Castelein R.J.M.
      • Kummer J.A.
      • et al.
      Micro-CT quantification of subchondral endplate changes in intervertebral disc degeneration.
      , similar to degenerated cartilage
      • Cox L.G.E.
      • van Donkelaar C.C.
      • van Rietbergen B.
      • Emans P.J.
      • Ito K.
      Decreased bone tissue mineralization can partly explain subchondral sclerosis observed in osteoarthritis.
      . Changes in endplate and subchondral bone morphology (e.g., fractures or endplate sclerosis) have also been implicated as preceding intervertebral disc generation (by decompression of the nucleus
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Adams M.A.
      • Dolan P.
      Intervertebral disc degeneration: evidence for two distinct phenotypes.
      • van Dieën J.H.
      • Weinans H.
      • Toussaint H.M.
      Fractures of the lumbar vertebral endplate in the etiology of low back pain: a hypothesis on the causative role of spinal compression in a specific low back pain.
      • Przybyla A.
      • Pollintine P.
      • Bedzinski R.
      • Adams M.A.
      Outer annulus tears have less effect than endplate fracture on stress distributions inside intervertebral discs: relevance to disc degeneration.
      or impairment of nutrition
      • Urban J.P.G.
      • Smith S.
      • Fairbank J.C.T.
      Nutrition of the intervertebral disc.
      • Benneker L.M.
      • Heini P.F.
      • Alini M.
      • Anderson S.E.
      • Ito K.
      2004 Young Investigator Award Winner: vertebral endplate marrow contact channel occlusions and intervertebral disc degeneration.
      • Roberts S.
      • Urban J.P.
      • Evans H.
      • Eisenstein S.M.
      Transport properties of the human cartilage endplate in relation to its composition and calcification..
      , respectively). Overall, the endplate can be deemed an important part of the intervertebral disc, because damage to the endplate is strongly related to both intervertebral disc degeneration and low back pain
      • Wang Y.
      • Videman T.
      • Battié M.C.
      ISSLS prize winner: lumbar vertebral endplate lesions: associations with disc degeneration and back pain history.
      • Wang Y.
      • Videman T.
      • Battié M.C.
      Lumbar vertebral endplate lesions: prevalence, classification, and association with age.
      • Mok F.P.S.
      • Samartzis D.
      • Karppinen J.
      • Luk K.D.K.
      • Fong D.Y.T.
      • Cheung K.M.C.
      ISSLS prize winner: prevalence, determinants, and association of Schmorl nodes of the lumbar spine with disc degeneration: a population-based study of 2449 individuals.
      • Lotz J.C.
      • Fields A.J.
      • Liebenberg E.C.
      The role of the vertebral end plate in low back pain.
      .
      Overall, a degenerated intervertebral disc differs from a non-degenerated intervertebral disc in that there is a marked loss of disc height, a fibrous dehydrated nucleus, in- ward and out-ward buckling of annulus fibres, extensive endplate damage, and sclerosis of the subchondral bone.

      Degeneration of the intervertebral disc; an interaction between cells, extracellular matrix, and biomechanics

      The nucleus pulposus radiographically shows the most extensive changes in intervertebral disc degeneration
      • Iatridis J.C.
      • Nicoll S.B.
      • Michalek A.J.
      • Walter B.A.
      • Gupta M.S.
      Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?.
      • Weiler C.
      • Schietzsch M.
      • Kirchner T.
      • Nerlich A.G.
      • Boos N.
      • Wuertz K.
      Age-related changes in human cervical, thoracal and lumbar intervertebral disc exhibit a strong intra-individual correlation.
      • Pfirrmann C.W.
      • Metzdorf A.
      • Zanetti M.
      • Hodler J.
      • Boos N.
      Magnetic resonance classification of lumbar intervertebral disc degeneration.
      , and it is therefore the most thoroughly investigated. Both the annulus fibrosus and cartilaginous endplates have received attention in their relationship with intervertebral disc degeneration; however, changes in these structures are less well documented
      • Boos N.
      • Weissbach S.
      • Rohrbach H.
      • Weiler C.
      • Spratt K.F.
      • Nerlich A.G.
      Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science.
      • Thompson J.P.
      • Pearce R.H.
      • Schechter M.T.
      • Adams M.E.
      • Tsang I.K.
      • Bishop P.B.
      Preliminary evaluation of a scheme for grading the gross morphology of the human intervertebral disc.
      . Therefore, this section will focus on the changes in the nucleus pulposus, followed by a short summary of the effect of nucleus degeneration on the annulus and endplates, and vice versa. We will discuss the cells in the nucleus pulposus and their interaction with the surrounding matrix; the effect of the shift of matrix composition on the biomechanical behaviour; and the subsequent effect of biomechanical stresses on cellular physiology. This will show the progressive nature of intervertebral disc degeneration to be a positive feedback loop as shown in it's basic conceptual form (Fig. 1).

      Cells: from notochordal cells to nuclear chondrocytes

      In the human nucleus pulposus, notochordal cells that are present from the early embryonic formation of the intervertebral disc
      • Hunter C.J.
      • Matyas J.R.
      • Duncan N.A.
      The notochordal cell in the nucleus pulposus: a review in the context of tissue engineering.
      • Hayes A.J.
      • Benjamin M.
      • Ralphs J.R.
      Role of actin stress fibres in the development of the intervertebral disc: cytoskeletal control of extracellular matrix assembly.
      show a gradual transition towards chondrocyte-like cells in the first decade of life
      • Boos N.
      • Weissbach S.
      • Rohrbach H.
      • Weiler C.
      • Spratt K.F.
      • Nerlich A.G.
      Classification of age-related changes in lumbar intervertebral discs: 2002 Volvo Award in basic science.
      • Zhao C.-Q.
      • Wang L.-M.
      • Jiang L.-S.
      • Dai L.-Y.
      The cell biology of intervertebral disc aging and degeneration.
      . Recently murine fate mapping studies demonstrated that the mature chondrocyte-like cells in the nucleus pulposus cells are derived from the embryonic notochord
      • McCann M.R.
      • Tamplin O.J.
      • Rossant J.
      • Seguin C.A.
      Tracing notochord-derived cells using a Noto-cre mouse: implications for intervertebral disc development.
      • Choi K.S.
      • Cohn M.J.
      • Harfe B.D.
      Identification of nucleus pulposus precursor cells and notochordal remnants in the mouse: Implications for disk degeneration and chordoma formation.
      . These mature nuclear chondrocytes produce collagen type I, but reduced amounts of water-attracting proteoglycans and collagen type II42. Thus, the transition of the cell population in the nucleus pulposus from predominantly notochordal cells to chondrocyte-like cells leads to a decrease in proteoglycan synthesis and therefore affects the potential of the nucleus pulposus to maintain it's structure and composition
      • Urban J.P.G.
      The nucleus of the intervertebral disc from development to degeneration.
      • Sakai D.
      • Nakamura Y.
      • Nakai T.
      • Mishima T.
      • Kato S.
      • Grad S.
      • et al.
      Exhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc.
      .

      Cells – extracellular matrix: from anabolism to catabolism

      In the degenerating intervertebral disc, there is a progressive increase in the expression of inflammatory cytokines like IL-1 and TNFα
      • Richardson S.M.
      • Doyle P.
      • Minogue B.M.
      • Gnanalingham K.
      • Hoyland J.A.
      Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc.
      • Purmessur D.
      • Walter B.A.
      • Roughley P.J.
      • Laudier D.M.
      • Hecht A.C.
      • Iatridis J.
      A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift.
      • Le Maitre C.L.
      • Freemont A.J.
      • Hoyland J.A.
      The role of interleukin-1 in the pathogenesis of human intervertebral disc degeneration.
      . These cytokines, expressed by nucleus cells, up-regulate matrix remodelling involved in intervertebral disc degeneration
      • Richardson S.M.
      • Doyle P.
      • Minogue B.M.
      • Gnanalingham K.
      • Hoyland J.A.
      Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc.
      • Binch A.
      • Cole A.A.
      • Breakwell L.M.
      • Michael A.
      • Chiverton N.
      • Cross A.K.
      • et al.
      Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration.
      . Matrix remodelling by the nucleus cells is mainly mediated by two families of enzymes: Matrix Metallo Proteinases (MMP) and A Disintegrin And Metalloproteinases with Thrombospondin Motifs proteins (ADAM-TS)
      • Weiler C.
      • Nerlich A.G.
      • Zipperer J.
      • Bachmeier B.E.
      • Boos N.
      2002 SSE Award Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption.
      • V Vo N.
      • 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.
      . Some non-proteolytic degradation is also present due to glycation
      • Roughley P.J.
      • Geng Y.
      • Mort J.S.
      The non-aggregated aggrecan in the human intervertebral disc can arise by a non-proteolytic mechanism.
      . In later stages of disc degeneration, inflammatory cytokines also enhance neurovascular in-growth and pain response
      • Richardson S.M.
      • Doyle P.
      • Minogue B.M.
      • Gnanalingham K.
      • Hoyland J.A.
      Increased expression of matrix metalloproteinase-10, nerve growth factor and substance P in the painful degenerate intervertebral disc.
      • Binch A.
      • Cole A.A.
      • Breakwell L.M.
      • Michael A.
      • Chiverton N.
      • Cross A.K.
      • et al.
      Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration.
      . Altogether, there is a progressive reduction in the expression of proteoglycans and collagen type II genes with increasing degeneration
      • Weiler C.
      • Nerlich A.G.
      • Zipperer J.
      • Bachmeier B.E.
      • Boos N.
      2002 SSE Award Competition in Basic Science: expression of major matrix metalloproteinases is associated with intervertebral disc degradation and resorption.
      • Antoniou J.
      • Steffen T.
      • Nelson F.
      • Winterbottom N.
      • Hollander A.P.
      • Poole R.A.
      • et al.
      The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.
      • Weiler C.
      • Schietzsch M.
      • Kirchner T.
      • Nerlich A.G.
      • Boos N.
      • Wuertz K.
      Age-related changes in human cervical, thoracal and lumbar intervertebral disc exhibit a strong intra-individual correlation.
      • Sztrolovics R.
      • Alini M.
      • Roughley P.J.
      • Mort J.S.
      Aggrecan degradation in human intervertebral disc and articular cartilage.
      . Simultaneously, collagen type I expression is increased, which indicates a change in matrix stresses
      • Carter D.R.
      • Wong M.
      Modelling cartilage mechanobiology.
      .

      Extracellular matrix: from proteoglycans to collagen type I

      The nucleus pulposus extracellular matrix consists of proteoglycans and collagens, and aggrecan is by far the most abundant proteoglycan in the nucleus
      • Roughley P.J.
      • Melching L.I.
      • Heathfield T.F.
      • Pearce R.H.
      • Mort J.S.
      The structure and degradation of aggrecan in human intervertebral disc.
      . Proteoglycans have a negative charge, which causes an osmotic pressure of 420–450 mOsm
      • Ishihara H.
      • Warensjo K.
      • Roberts S.
      • Urban J.P.
      Proteoglycan synthesis in the intervertebral disk nucleus: the role of extracellular osmolality.
      . This osmotic pressure attracts and binds water to the extracellular matrix. In degeneration, aggrecan is cleaved from the hyaluronic acid backbone
      • Latridis J.C.
      • Godburn K.
      • Wuertz K.
      • Alini M.
      • Roughley P.J.
      Region-dependent aggrecan degradation patterns in the rat intervertebral disc are affected by mechanical loading in vivo.
      • Jim B.
      • Steffen T.
      • Moir J.
      • Roughley P.
      • Haglund L.
      Development of an intact intervertebral disc organ culture system in which degeneration can be induced as a prelude to studying repair potential.
      . Cleaved aggrecan fractions do not aggregate
      • Roughley P.J.
      • Melching L.I.
      • Heathfield T.F.
      • Pearce R.H.
      • Mort J.S.
      The structure and degradation of aggrecan in human intervertebral disc.
      , making them less effective in binding water. Furthermore, there is a shift of predominantly collagen type II to collagen type I in the nucleus
      • Antoniou J.
      • Steffen T.
      • Nelson F.
      • Winterbottom N.
      • Hollander A.P.
      • Poole R.A.
      • et al.
      The human lumbar intervertebral disc: evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration.
      . Overall, the biochemical content of the extracellular matrix changes from predominantly proteoglycans and collagen type II to a more fibrous tissue consisting primarily of collagen type I, resulting in a loss of water-binding potential.

      Extracellular matrix – biomechanics: a reduction in intradiscal pressure

      In healthy discs, the negative charge of the proteoglycans generates an osmotic potential, which is translated into a biomechanical hydrostatic pressure through the attraction of water. This intradiscal pressure is approximately 0.1–0.24 MPa when lying supine, and increases linearly with loading of the disc
      • Sato K.
      • Kikuchi S.
      • Yonezawa T.
      In vivo intradiscal pressure measurement in healthy individuals and in patients with ongoing back problems.
      • Wilke H.J.
      • Neef P.
      • Caimi M.
      • Hoogland T.
      • Claes L.E.
      New in vivo measurements of pressures in the intervertebral disc in daily life.
      • Nachemson A.
      The load on lumbar disks in different positions of the body.
      • Chan W.C.W.
      • Sze K.L.
      • Samartzis D.
      • Leung V.Y.L.
      • Chan D.
      Structure and biology of the intervertebral disk in health and disease.
      , up to more than 2.0 MPa
      • Wilke H.J.
      • Neef P.
      • Caimi M.
      • Hoogland T.
      • Claes L.E.
      New in vivo measurements of pressures in the intervertebral disc in daily life.
      . The quantity of bound water can vary, which changes the intrinsic intradiscal pressure
      • Urban J.P.
      • McMullin J.F.
      Swelling pressure of the lumbar intervertebral discs: influence of age, spinal level, composition, and degeneration.
      . In healthy discs, this decrease or increase of bound water is due to poro-elastic fluid flow upon loading or unloading of the disc, respectively
      • Vergroesen P.-P.A.
      • van der Veen A.J.
      • van Royen B.J.
      • Kingma I.
      • Smit T.H.
      Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.
      • Hwang D.
      • Gabai A.S.
      • Yu M.
      • Yew A.G.
      • Hsieh A.H.
      Role of load history in intervertebral disc mechanics and intradiscal pressure generation.
      . In degenerating discs, the increased fragmentation of aggrecan reduces its effective negative charge, which decreases intradiscal pressure
      • Sato K.
      • Kikuchi S.
      • Yonezawa T.
      In vivo intradiscal pressure measurement in healthy individuals and in patients with ongoing back problems.
      and the ability to retain water under compressive forces
      • Lee H.-Y.
      • Han L.
      • Roughley P.J.
      • Grodzinsky A.J.
      • Ortiz C.
      Age-related nanostructural and nanomechanical changes of individual human cartilage aggrecan monomers and their glycosaminoglycan side chains.
      , which is reflected in the reduction of disc height
      • Iatridis J.C.
      • Nicoll S.B.
      • Michalek A.J.
      • Walter B.A.
      • Gupta M.S.
      Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?.
      • Vergroesen P.-P.A.
      • van der Veen A.J.
      • van Royen B.J.
      • Kingma I.
      • Smit T.H.
      Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.
      . The effect of a reduction of collagen type II and an increase of collagen type I on the biomechanical function of the nucleus matrix is unknown. However, as collagen type II is more compliant than collagen type I, an increase of nuclear shear stresses is expected.

      Biomechanics: from hydrostatic pressure to shear stress

      Intradiscal pressure is essential for the maintenance of biomechanical behaviour of the intervertebral disc. Intradiscal pressure tensions annulus fibres, and supports the endplate, and as such is the main determinant of disc height and stiffness in axial compression
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      • Vergroesen P.-P.A.
      • van der Veen A.J.
      • van Royen B.J.
      • Kingma I.
      • Smit T.H.
      Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.
      . In degenerated intervertebral discs, disc height and axial compliance are reduced, and radial bulge is increased
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      • Vergroesen P.-P.A.
      • van der Veen A.J.
      • van Royen B.J.
      • Kingma I.
      • Smit T.H.
      Intradiscal pressure depends on recent loading and correlates with disc height and compressive stiffness.
      • Masuoka K.
      • Michalek A.J.
      • MacLean J.J.
      • Stokes I.A.F.
      • Iatridis J.C.
      Different effects of static versus cyclic compressive loading on rat intervertebral disc height and water loss in vitro.
      . Another effect of the reduced intradiscal pressure in the intervertebral disc is the disturbed stress distribution found in degenerated discs
      • Adams M.A.
      • Roughley P.J.
      What is intervertebral disc degeneration, and what causes it?.
      • Adams M.A.
      • McMillan D.W.
      • Green T.P.
      • Dolan P.
      Sustained loading generates stress concentrations in lumbar intervertebral discs.
      . This disturbance in stress distribution generates stress concentrations, which increases the risk of endplate fractures or Schmorl's nodes, which are increasingly seen with disc degeneration
      • Mok F.P.S.
      • Samartzis D.
      • Karppinen J.
      • Luk K.D.K.
      • Fong D.Y.T.
      • Cheung K.M.C.
      ISSLS prize winner: prevalence, determinants, and association of Schmorl nodes of the lumbar spine with disc degeneration: a population-based study of 2449 individuals.
      .
      A reduction in intradiscal pressure leads to increased shear stresses in both the nucleus pulposus and the annulus fibrosus upon axial compression of the spine
      • Urban J.P.G.
      The role of the physicochemical environment in determining disc cell behaviour.
      • Hwang D.
      • Gabai A.S.
      • Yu M.
      • Yew A.G.
      • Hsieh A.H.
      Role of load history in intervertebral disc mechanics and intradiscal pressure generation.
      . Due to loss of tension in the annulus fibrosus, motion segments with reduced intradiscal pressure also have an enlarged neutral zone in shear, bending, and torsion
      • Inoue N.
      • Espinoza Orías A.A.
      Biomechanics of intervertebral disk degeneration.
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      • Panjabi M.M.
      Clinical spinal instability and low back pain.
      • Zirbel S.A.
      • Stolworthy D.K.
      • Howell L.L.
      • Bowden A.E.
      Intervertebral disc degeneration alters lumbar spine segmental stiffness in all modes of loading under a compressive follower load.
      • Ellingson A.M.
      • Mehta H.
      • Polly D.W.
      • Ellermann J.
      • Nuckley D.J.
      Disc degeneration assessed by quantitative T2* (T2 star) correlated with functional lumbar mechanics.
      • Quint U.
      • Wilke H.-J.
      Grading of degenerative disk disease and functional impairment: imaging versus patho-anatomical findings.
      • Galbusera F.
      • van Rijsbergen M.
      • Ito K.
      • Huyghe J.M.
      • Brayda-Bruno M.
      • Wilke H.-J.
      Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility.
      . The resultant changes in bending and torsion behaviour of the motion segment may further increase shear stresses in the nucleus and remodelling of the extracellular matrix. Thus, the reduction of intradiscal pressure reduces disc height; increases stress concentrations within the disc; and increases shear forces in the nucleus.

      Biomechanics – cells: a change in matrix stresses alters cellular physiology

      The concept that the mechanical environment of cells is important for cell function is not new. In 1862, Hueter and Volkmann independently hypothesized that mechanical stimuli directly influence cellular function and matrix synthesis in bone and joints due to local differences in tension and pressure
      • Hueter C.
      Anatomische Studien an den Extremitätengelenken Neugeborener und Erwachsener.
      • Volkmann R.
      Chirurgische Erfahrungen über Knochenverbiegungen und Knochenwachsthum.
      . Today, the effect of biomechanical forces on cellular function is known as mechanobiology
      • Adams M.A.
      • Dolan P.
      • McNally D.S.
      The internal mechanical functioning of intervertebral discs and articular cartilage, and its relevance to matrix biology.
      • van der Meulen M.C.H.
      • Huiskes R.
      Why mechanobiology? A survey article..
      • Hsieh A.H.
      • Twomey J.D.
      Cellular mechanobiology of the intervertebral disc: new directions and approaches.
      • Chan S.C.W.
      • Ferguson S.J.
      • Gantenbein-Ritter B.
      The effects of dynamic loading on the intervertebral disc.
      . Several research groups have shown that a distinct compressive force on the spinal motion segment, both in vivo and ex vivo, can cause catabolic, anabolic and inflammatory cell responses in the intervertebral disc
      • Paul C.P.L.
      • Schoorl T.
      • Zuiderbaan H.A.
      • Zandieh Doulabi B.
      • van der Veen A.J.
      • van de Ven P.M.
      • et al.
      Dynamic and static overloading induce early degenerative processes in caprine lumbar intervertebral discs.
      • Wuertz K.
      • Godburn K.
      • MacLean J.J.
      • Barbir A.
      • Stinnet Donnelly J.
      • Roughley P.J.
      • et al.
      In vivo remodeling of intervertebral discs in response to short- and long-term dynamic compression.
      • Wang D.-L.
      • Jiang S.-D.
      • Dai L.-Y.
      Biologic response of the intervertebral disc to static and dynamic compression in vitro.
      • Haglund L.
      • Moir J.
      • Beckman L.
      • Mulligan K.R.
      • Jim B.
      • Ouellet J.A.
      • et al.
      Development of a bioreactor for axially loaded intervertebral disc organ culture.
      • Korecki C.L.
      • MacLean J.J.
      • Iatridis J.C.
      Dynamic compression effects on intervertebral disc mechanics and biology.
      • Hartman R.A.
      • Bell K.M.
      • Debski R.E.
      • Kang J.D.
      • Sowa G.A.
      Novel ex-vivo mechanobiological intervertebral disc culture system.
      . Also the temporal characteristics of loading are important as cyclic loading has been shown to be beneficial as opposed to static loading
      • Paul C.P.L.
      • Zuiderbaan H.A.
      • Zandieh Doulabi B.
      • van der Veen A.J.
      • van de Ven P.M.
      • Smit T.H.
      • et al.
      Simulated-physiological loading conditions preserve biological and mechanical properties of caprine lumbar intervertebral discs in ex vivo culture.
      • Wang D.-L.
      • Jiang S.-D.
      • Dai L.-Y.
      Biologic response of the intervertebral disc to static and dynamic compression in vitro.
      • Chan S.C.W.
      • Walser J.
      • Käppeli P.
      • Shamsollahi M.J.
      • Ferguson S.J.
      • Gantenbein-Ritter B.
      Region specific response of intervertebral disc cells to complex dynamic loading: an organ culture study using a dynamic torsion-compression bioreactor.
      • Walsh A.J.L.
      • Lotz J.C.
      Biological response of the intervertebral disc to dynamic loading.
      . As a result, the relationship between mechanical behaviour and cell function is argued to be a pivotal component of intervertebral disc function and dysfunction
      • Hsieh A.H.
      • Twomey J.D.
      Cellular mechanobiology of the intervertebral disc: new directions and approaches.
      • Setton L.A.
      • Chen J.
      Cell mechanics and mechanobiology in the intervertebral disc.
      • Chan S.C.W.
      • Ferguson S.J.
      • Gantenbein-Ritter B.
      The effects of dynamic loading on the intervertebral disc.
      • Lee C.R.
      • Iatridis J.C.
      • Poveda L.
      • Alini M.
      In vitro organ culture of the bovine intervertebral disc: effects of vertebral endplate and potential for mechanobiology studies.
      .
      Cells throughout the intervertebral disc respond to changes in hydrostatic pressure. In the nucleus, the proteoglycan production at 0.3 MPa is roughly 20% higher than at 0.1 MPa
      • Handa T.
      • Ishihara H.
      • Ohshima H.
      • Osada R.
      • Tsuji H.
      • Obata K.
      Effects of hydrostatic pressure on matrix synthesis and matrix metalloproteinase production in the human lumbar intervertebral disc.
      • Ishihara H.
      • McNally D.S.
      • Urban J.P.
      • Hall A.C.
      Effects of hydrostatic pressure on matrix synthesis in different regions of the intervertebral disk.
      . Additionally, MMP-3 production is reduced, and tissue inhibitor of metallo proteins-1 (TIMP) production is increased
      • Handa T.
      • Ishihara H.
      • Ohshima H.
      • Osada R.
      • Tsuji H.
      • Obata K.
      Effects of hydrostatic pressure on matrix synthesis and matrix metalloproteinase production in the human lumbar intervertebral disc.
      • Ishihara H.
      • McNally D.S.
      • Urban J.P.
      • Hall A.C.
      Effects of hydrostatic pressure on matrix synthesis in different regions of the intervertebral disk.
      , which reduces remodelling of the extracellular matrix. This pressure sensing mechanism of nucleus cells appears to be impaired in cells from degenerated discs as they respond less anabolic to physiologic intradiscal pressure
      • Le Maitre C.L.
      • Frain J.
      • Fotheringham A.P.
      • Freemont A.J.
      • Hoyland J.A.
      Human cells derived from degenerate intervertebral discs respond differently to those derived from non-degenerate intervertebral discs following application of dynamic hydrostatic pressure.
      . Cells also respond to the osmotic pressure of the extracellular matrix, with an optimum proteoglycan production at pressures between 400 and 500 mOsm, and a reduced synthesis of aggrecan with declining or increasing osmotic pressure
      • Ishihara H.
      • Warensjo K.
      • Roberts S.
      • Urban J.P.
      Proteoglycan synthesis in the intervertebral disk nucleus: the role of extracellular osmolality.
      • van Dijk B.
      • Potier E.
      • Ito K.
      Culturing bovine nucleus pulposus explants by balancing medium osmolarity.
      • Wuertz K.
      • Urban J.P.G.
      • Klasen J.
      • Ignatius A.
      • Wilke H.-J.
      • Claes L.
      • et al.
      Influence of extracellular osmolarity and mechanical stimulation on gene expression of intervertebral disc cells.
      • Neidlinger-Wilke C.
      • Mietsch A.
      • Rinkler C.
      • Wilke H.-J.
      • Ignatius A.
      • Urban J.
      Interactions of environmental conditions and mechanical loads have influence on matrix turnover by nucleus pulposus cells.
      . A decline in osmotic pressure increases MMP-3 production
      • Neidlinger-Wilke C.
      • Mietsch A.
      • Rinkler C.
      • Wilke H.-J.
      • Ignatius A.
      • Urban J.
      Interactions of environmental conditions and mechanical loads have influence on matrix turnover by nucleus pulposus cells.
      , and precludes hypertrophy of the normally hyperosmotic nuclear chondrocytes
      • Urban J.P.G.
      The role of the physicochemical environment in determining disc cell behaviour.
      • Pritchard S.
      • Erickson G.R.
      • Guilak F.
      Hyperosmotically induced volume change and calcium signaling in intervertebral disk cells: the role of the actin cytoskeleton.
      . Thus, in degenerating intervertebral discs, the drop in intradiscal and osmotic pressure will reduce the anabolic stimulus and increase catabolic stimuli to the nuclear chondrocytes.
      The shift of hydrostatic pressure to shear stresses in the intervertebral disc has a distinct mechanobiological effect on the nuclear chondrocytes
      • Hwang D.
      • Gabai A.S.
      • Yu M.
      • Yew A.G.
      • Hsieh A.H.
      Role of load history in intervertebral disc mechanics and intradiscal pressure generation.
      • Kim J.
      • Yang S.-J.
      • Kim H.
      • Kim Y.
      • Park J.B.
      • Dubose C.
      • et al.
      Effect of shear force on intervertebral disc (IVD) degeneration: an in vivo rat study.
      • Smith R.L.
      • Carter D.R.
      • Schurman D.J.
      Pressure and shear differentially alter human articular chondrocyte metabolism: a review.
      . Similar to other load-bearing tissues like cartilage and bone, the increase in shear stress will initiate the formation of a fibrous tissue, rich in collagen type I
      • Hsieh A.H.
      • Twomey J.D.
      Cellular mechanobiology of the intervertebral disc: new directions and approaches.
      • Carter D.R.
      • Wong M.
      Modelling cartilage mechanobiology.
      • Smith R.L.
      • Carter D.R.
      • Schurman D.J.
      Pressure and shear differentially alter human articular chondrocyte metabolism: a review.
      • Lacroix D.
      • Prendergast P.J.
      A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading.
      . Furthermore, increased shear stress increases the production of nitric oxide by chondrocytes
      • Smith R.L.
      • Carter D.R.
      • Schurman D.J.
      Pressure and shear differentially alter human articular chondrocyte metabolism: a review.
      . Nitric oxide is a reactive oxygen metabolite that reduces proteoglycan production, and increases apoptosis in cartilage and in the intervertebral disc
      • Smith R.L.
      • Carter D.R.
      • Schurman D.J.
      Pressure and shear differentially alter human articular chondrocyte metabolism: a review.
      • Liu G.Z.
      • Ishihara H.
      • Osada R.
      • Kimura T.
      • Tsuji H.
      Nitric oxide mediates the change of proteoglycan synthesis in the human lumbar intervertebral disc in response to hydrostatic pressure.
      • Hsieh A.H.
      • Walsh A.J.L.
      • Cheng L.Y.
      • Lotz J.C.
      Apoptosis corresponds with disc strain environment during dynamic compression.
      . Thus, reduction of intradiscal pressure increases shear stresses in the nucleus, and both may accelerate degeneration in the intervertebral disc.

      Nucleus homeostasis depends on endplate and annulus integrity

      Although we have focussed on the nucleus pulposus in this section, the homeostasis of the nucleus is dependent on the confines of a functional annulus and intact endplates
      • van Dijk B.
      • Potier E.
      • Ito K.
      Culturing bovine nucleus pulposus explants by balancing medium osmolarity.
      • Wang P.
      • Yang L.
      • Hsieh A.H.
      Nucleus pulposus cell response to confined and unconfined compression implicates mechanoregulation by fluid shear stress.
      . If damage to either of these structures occurs, the nucleus is decompressed
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Iatridis J.C.
      • Weidenbaum M.
      • Setton L.A.
      • Mow V.C.
      Is the nucleus pulposus a solid or a fluid? Mechanical behaviors of the nucleus pulposus of the human intervertebral disc.
      , and exposed to inflammatory cells from outside the disc
      • Binch A.
      • Cole A.A.
      • Breakwell L.M.
      • Michael A.
      • Chiverton N.
      • Cross A.K.
      • et al.
      Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration.
      . Both these effects will result in the degenerative cascade described above. Conversely, if the nucleus is degenerated, this will also affect the annulus and the endplates. In the annulus, the reduction of intradiscal pressure will reduce tension in annulus fibres
      • Brinckmann P.
      • Grootenboer H.
      Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs.
      and increase in- and out-ward bulging
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Stefanakis M.
      • Luo J.
      • Pollintine P.
      • Dolan P.
      • Adams M.A.
      ISSLS prize winner: mechanical influences in progressive intervertebral disc degeneration.
      . This bulging can increase shear forces between laminae
      • Iatridis J.C.
      • Gwynn I.A.P.
      Mechanisms for mechanical damage in the intervertebral disc annulus fibrosus.
      , leading to de-lamination of the translamellar bridges
      • Schollum M.L.
      • Robertson P.A.
      • Broom N.D.
      ISSLS prize winner: microstructure and mechanical disruption of the lumbar disc annulus: part I: a microscopic investigation of the translamellar bridging network.
      , and consecutive risk of tears
      • Stefanakis M.
      • Luo J.
      • Pollintine P.
      • Dolan P.
      • Adams M.A.
      ISSLS prize winner: mechanical influences in progressive intervertebral disc degeneration.
      . In the endplates, the loss of annulus tension and the reduced stress distribution by the nucleus will alter the biomechanical stresses on the endplates
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Iatridis J.C.
      • Nicoll S.B.
      • Michalek A.J.
      • Walter B.A.
      • Gupta M.S.
      Role of biomechanics in intervertebral disc degeneration and regenerative therapies: what needs repairing in the disc and what are promising biomaterials for its repair?.
      , which may be the cause of endplate sclerosis, fractures, or Schmorl's nodes
      • Mok F.P.S.
      • Samartzis D.
      • Karppinen J.
      • Luk K.D.K.
      • Fong D.Y.T.
      • Cheung K.M.C.
      ISSLS prize winner: prevalence, determinants, and association of Schmorl nodes of the lumbar spine with disc degeneration: a population-based study of 2449 individuals.
      .
      In summary, the interaction of cells, extracellular matrix and biomechanical stress is instrumental in homeostasis of the intervertebral disc. In intervertebral disc degeneration this balance is disturbed. If the cells do not receive the proper mechanical and chemical cues they will stop producing, or even start degrading proteoglycans. A reduction in proteoglycans will lead to a drop of the intradiscal pressure, which will alter the biomechanical stresses on the cells. From this, one can deduce a positive feedback loop of intervertebral disc degeneration, which contains cells, extracellular matrix, and biomechanics: the degenerative circle (Fig. 2).
      Figure thumbnail gr2
      Fig. 2The degenerative circle of intervertebral disc degeneration. Homeostasis of the intervertebral disc is dependent on the interaction of cells, extracellular matrix and biomechanical stress. If this balance is disturbed, the cells stop producing proteoglycans, this will give a reduction in hydrostatic pressure and increase shear forces on the cells. An increase of shear forces further decreases the production of proteoglycans, leading to progressive degeneration.

      Application of the degenerative circle

      The degenerative circle illustrates the progressive nature of intervertebral disc degeneration, but can also explain the different aetiologies of intervertebral disc degeneration. In this section, we investigate the application of the degenerative circle in understanding human epidemiology and animal models for intervertebral disc degeneration. In human epidemiology, aberrant biomechanics (e.g., frequent lifting
      • Seidler A.
      • Euler U.
      • Bolm-Audorff U.
      • Ellegast R.
      • Grifka J.
      • Haerting J.
      • et al.
      Physical workload and accelerated occurrence of lumbar spine diseases: risk and rate advancement periods in a German multicenter case-control study.
      ); chemical stress to cells (e.g., smoking
      • Battié M.C.
      • Videman T.
      • Gill K.
      • Moneta G.B.
      • Nyman R.
      • Kaprio J.
      • et al.
      1991 Volvo Award in clinical sciences. Smoking and lumbar intervertebral disc degeneration: an MRI study of identical twins.
      ); or damage to the extracellular matrix (e.g., discography
      • Carragee E.J.
      • Don A.S.
      • Hurwitz E.L.
      • Cuellar J.M.
      • Carrino J.A.
      • Carrino J.
      • et al.
      2009 ISSLS prize winner: does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study.
      ); all lead to intervertebral disc degeneration. Additionally, induction of intervertebral disc degeneration in animal models can be effectuated through: altered disc biomechanics, changes to cell physiology, and damage to the nucleus, annulus, or endplates. This section will provide examples of the initiation of degeneration through each of the three domains, i.e., biomechanics, cells, and extracellular matrix. By applying the model from different angles, we aim to infer the generic nature of the degenerative circle, as all discussed examples of human epidemiological occurrence of disc degeneration and animal models apparently lead to a similar degeneration of the intervertebral disc (Fig. 3). To illustrate the independence of starting at a specific point in the circle, we start this section by discussing biomechanics.
      Figure thumbnail gr3
      Fig. 3The efficacy of animal models applied to the degenerative circle. Intervertebral disc degeneration can be induced through any of the three main elements of the degenerative circle, which further indicates a positive feedback loop.

      Biomechanics: induction of degeneration

      In literature the biomechanical “wear and tear” has long been thought to be a major cause of intervertebral disc degeneration
      • Battié M.C.
      • Videman T.
      • Kaprio J.
      • Gibbons L.E.
      • Gill K.
      • Manninen H.
      • et al.
      The Twin Spine Study: contributions to a changing view of disc degeneration.
      • Bakker E.W.P.
      • Verhagen A.P.
      • van Trijffel E.
      • Lucas C.
      • Koes B.W.
      Spinal mechanical load as a risk factor for low back pain: a systematic review of prospective cohort studies.
      , mainly because low back pain and degeneration occur, more frequently than in the general population, in manual labour workers
      • Luoma K.
      • Riihimäki H.
      • Luukkonen R.
      • Raininko R.
      • Viikari-Juntura E.
      • Lamminen A.
      Low back pain in relation to lumbar disc degeneration.
      , machine drivers
      • Luoma K.
      • Riihimäki H.
      • Luukkonen R.
      • Raininko R.
      • Viikari-Juntura E.
      • Lamminen A.
      Low back pain in relation to lumbar disc degeneration.
      , soldiers carrying loads
      • Roy T.C.
      • Lopez H.P.
      • Piva S.R.
      Loads worn by soldiers predict episodes of low back pain during deployment to Afghanistan.
      , but also in elite athletes
      • Swärd L.
      • Hellström M.
      • Jacobsson B.
      • Nyman R.
      • Peterson L.
      Disc degeneration and associated abnormalities of the spine in elite gymnasts. A magnetic resonance imaging study.
      • Taunton J.E.
      • Ryan M.B.
      • Clement D.B.
      • McKenzie D.C.
      • Lloyd-Smith D.R.
      • Zumbo B.D.
      A retrospective case-control analysis of 2002 running injuries.
      • Dubravcic-Simunjak S.
      • Pecina M.
      • Kuipers H.
      • Moran J.
      • Haspl M.
      The incidence of injuries in elite junior figure skaters.
      . Interestingly, all astronauts experience low back pain upon the exposure to microgravity, and on their re-entry
      • V Sayson J.
      • Hargens A.R.
      Pathophysiology of low back pain during exposure to microgravity.
      • Johnston S.L.
      • Campbell M.R.
      • Scheuring R.
      • Feiveson A.H.
      Risk of herniated nucleus pulposus among U.S. Astronauts.
      , which both may be caused by over-pressurization of the nucleus. Although genetic research has nuanced the role of biomechanical factors in intervertebral disc degeneration
      • Battié M.C.
      • Videman T.
      • Kaprio J.
      • Gibbons L.E.
      • Gill K.
      • Manninen H.
      • et al.
      The Twin Spine Study: contributions to a changing view of disc degeneration.
      , there still is a link between high loading on the low back and both intervertebral disc degeneration and low back pain
      • Wang Y.
      • Videman T.
      • Battié M.C.
      ISSLS prize winner: lumbar vertebral endplate lesions: associations with disc degeneration and back pain history.
      • Luoma K.
      • Riihimäki H.
      • Luukkonen R.
      • Raininko R.
      • Viikari-Juntura E.
      • Lamminen A.
      Low back pain in relation to lumbar disc degeneration.
      • Wang Y.
      • Videman T.
      • Battié M.C.
      Lumbar vertebral endplate lesions: prevalence, classification, and association with age.
      • Seidler A.
      • Bergmann A.
      • Jäger M.
      • Ellegast R.
      • Ditchen D.
      • Elsner G.
      • et al.
      Cumulative occupational lumbar load and lumbar disc disease–results of a German multi-center case-control study (EPILIFT).
      • Coenen P.
      • Kingma I.
      • Boot C.R.L.
      • Bongers P.M.
      • van Dieën J.H.
      Cumulative mechanical low-back load at work is a determinant of low-back pain.
      • Coenen P.
      • Gouttebarge V.
      • van der Burght A.S.A.M.
      • van Dieën J.H.
      • Frings-Dresen M.H.W.
      • van der Beek A.J.
      • et al.
      The effect of lifting during work on low back pain: a health impact assessment based on a meta-analysis.
      .
      An abundance of animal models uses altered biomechanics to induce intervertebral disc degeneration, including: Tail suspension/Hind leg unloading
      • Holguin N.
      • Martin J.T.
      • Elliott D.M.
      • Judex S.
      Low-intensity vibrations partially maintain intervertebral disc mechanics and spinal muscle area during deconditioning.
      • Holguin N.
      • Uzer G.
      • Chiang F.-P.
      • Rubin C.
      • Judex S.
      Brief daily exposure to low-intensity vibration mitigates the degradation of the intervertebral disc in a frequency-specific manner.
      ; Tail or spinal compression
      • Wuertz K.
      • Godburn K.
      • MacLean J.J.
      • Barbir A.
      • Stinnet Donnelly J.
      • Roughley P.J.
      • et al.
      In vivo remodeling of intervertebral discs in response to short- and long-term dynamic compression.
      • Yurube T.
      • Takada T.
      • Suzuki T.
      • Kakutani K.
      • Maeno K.
      • Doita M.
      • et al.
      Rat tail static compression model mimics extracellular matrix metabolic imbalances of matrix metalloproteinases, aggrecanases, and tissue inhibitors of metalloproteinases in intervertebral disc degeneration.
      • Hirata H.
      • Yurube T.
      • Kakutani K.
      • Maeno K.
      • Takada T.
      • Yamamoto J.
      • et al.
      A rat tail temporary static compression model reproduces different stages of intervertebral disc degeneration with decreased notochordal cell phenotype.
      • Miyagi M.
      • Ishikawa T.
      • Kamoda H.
      • Suzuki M.
      • Murakami K.
      • Shibayama M.
      • et al.
      ISSLS prize winner: disc dynamic compression in rats produces long-lasting increases in inflammatory mediators in discs and induces long-lasting nerve injury and regeneration of the afferent fibers innervating discs: a pathomechanism for chronic discogenic low back pain.
      • Kroeber M.W.
      • Unglaub F.
      • Wang H.
      • Schmid C.
      • Thomsen M.
      • Nerlich A.
      • et al.
      New in vivo animal model to create intervertebral disc degeneration and to investigate the effects of therapeutic strategies to stimulate disc regeneration.
      ; tail bending
      • Court C.
      • Colliou O.K.
      • Chin J.R.
      • Liebenberg E.
      • Bradford D.S.
      • Lotz J.C.
      The effect of static in vivo bending on the murine intervertebral disc.
      • Court C.
      • Chin J.R.
      • Liebenberg E.
      • Colliou O.K.
      • Lotz J.C.
      Biological and mechanical consequences of transient intervertebral disc bending.
      • Stokes I.A.F.
      • McBride C.
      • Aronsson D.D.
      • Roughley P.J.
      Metabolic effects of angulation, compression and reduced mobility on annulus fibrosis in a model of altered mechanical environment in scoliosis.
      ; spinal shear stress
      • Kim J.
      • Yang S.-J.
      • Kim H.
      • Kim Y.
      • Park J.B.
      • Dubose C.
      • et al.
      Effect of shear force on intervertebral disc (IVD) degeneration: an in vivo rat study.
      , and microgravity
      • Bailey J.F.
      • Hargens A.R.
      • Cheng K.K.
      • Lotz J.C.
      Effect of microgravity on the biomechanical properties of lumbar and caudal intervertebral discs in mice.
      • Pedrini-Mille A.
      • Maynard J.A.
      • Durnova G.N.
      • Kaplansky A.S.
      • Pedrini V.A.
      • Chung C.B.
      • et al.
      Effects of microgravity on the composition of the intervertebral disk.
      . These models show that although the intervertebral disc is left intact, the altered biomechanical load leads to a catabolic cell reaction and remodelling of the intervertebral disc matrix over time. Apparently, in animal models, it does not matter whether the disc is overloaded, unloaded or aberrantly loaded: altering the biomechanical environment of the intervertebral disc induces a catabolic cell reaction with detrimental effects on the extracellular matrix.

      Cells: induction of degeneration

      One of the most influential paradigms on intervertebral disc degeneration is that a reduction in nutrition of disc cells leads to a catabolic shift
      • Urban J.P.G.
      • Roberts S.
      Degeneration of the intervertebral disc.
      • Urban J.P.G.
      • Smith S.
      • Fairbank J.C.T.
      Nutrition of the intervertebral disc.
      • Kepler C.K.
      • Ponnappan R.K.
      • Tannoury C.A.
      • Risbud M.V.
      • Anderson D.G.
      The molecular basis of intervertebral disc degeneration.
      • Roberts S.
      • Urban J.P.
      • Evans H.
      • Eisenstein S.M.
      Transport properties of the human cartilage endplate in relation to its composition and calcification..
      . The hypothesis is that this is due to the sclerosis of the endplates, which limits endplate pores and subsequent vascular supply
      • Benneker L.M.
      • Heini P.F.
      • Alini M.
      • Anderson S.E.
      • Ito K.
      2004 Young Investigator Award Winner: vertebral endplate marrow contact channel occlusions and intervertebral disc degeneration.
      . It has been established that diffusion into the disc changes with progression of intervertebral disc degeneration
      • Rajasekaran S.
      • Babu J.N.
      • Arun R.
      • Armstrong B.R.W.
      • Shetty A.P.
      • Murugan S.
      ISSLS prize winner: a study of diffusion in human lumbar discs: a serial magnetic resonance imaging study documenting the influence of the endplate on diffusion in normal and degenerate discs.
      . However, the origin of endplate sclerosis should be further elucidated to determine whether endplate sclerosis is in fact the cause, or merely an effect of degeneration due to altered biomechanical stresses in the endplates. Other risk factors like smoking
      • Battié M.C.
      • Videman T.
      • Kaprio J.
      • Gibbons L.E.
      • Gill K.
      • Manninen H.
      • et al.
      The Twin Spine Study: contributions to a changing view of disc degeneration.
      • Battié M.C.
      • Videman T.
      • Gill K.
      • Moneta G.B.
      • Nyman R.
      • Kaprio J.
      • et al.
      1991 Volvo Award in clinical sciences. Smoking and lumbar intervertebral disc degeneration: an MRI study of identical twins.
      and diabetes mellitus
      • Lotan R.
      • Oron A.
      • Anekstein Y.
      • Shalmon E.
      • Mirovsky Y.
      Lumbar stenosis and systemic diseases: is there any relevance?.
      , most likely induce disc degeneration by their effect on cellular physiology. Interestingly, these risk factors may also affect the nutrition of the nuclear chondrocytes by their detrimental effects on microcirculation
      • Kepler C.K.
      • Ponnappan R.K.
      • Tannoury C.A.
      • Risbud M.V.
      • Anderson D.G.
      The molecular basis of intervertebral disc degeneration.
      • Devaraj S.
      • Cheung A.T.
      • Jialal I.
      • Griffen S.C.
      • Nguyen D.
      • Glaser N.
      • et al.
      Evidence of increased inflammation and microcirculatory abnormalities in patients with type 1 diabetes and their role in microvascular complications.
      • Sørensen L.T.
      • Jørgensen S.
      • Petersen L.J.
      • Hemmingsen U.
      • Bülow J.
      • Loft S.
      • et al.
      Acute effects of nicotine and smoking on blood flow, tissue oxygen, and aerobe metabolism of the skin and subcutis.
      • Pellaton C.
      • Kubli S.
      • Feihl F.
      • Waeber B.
      Blunted vasodilatory responses in the cutaneous microcirculation of cigarette smokers.
      • 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.
      . Additional to the effects of nutrition, low-grade infection could possibly trigger the cells to degrade the matrix of the intervertebral disc
      • Alpantaki K.
      • Katonis P.
      • Hadjipavlou A.G.
      • Spandidos D.A.
      • Sourvinos G.
      Herpes virus infection can cause intervertebral disc degeneration: a causal relationship?.
      • Albert H.B.
      • Sorensen J.S.
      • Christensen B.S.
      • Manniche C.
      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.
      , similar to arthritic diseases
      • Carter J.D.
      • Gerard H.C.
      • Whittum-Hudson J.A.
      • Hudson A.P.
      The molecular basis for disease phenotype in chronic Chlamydia-induced arthritis.
      • Zeidler H.
      • Hudson A.P.
      New insights into Chlamydia and arthritis. Promise of a cure?.
      • Alvarez-Lafuente R.
      • Fernández-Gutiérrez B.
      • de Miguel S.
      • Jover J.A.
      • Rollin R.
      • Loza E.
      • et al.
      Potential relationship between herpes viruses and rheumatoid arthritis: analysis with quantitative real time polymerase chain reaction.
      .
      Intervertebral disc degeneration is found in mice which are exposed to tobacco smoke
      • Wang D.
      • Nasto L.A.
      • Roughley P.
      • Leme A.S.
      • Houghton A.M.
      • Usas A.
      • et al.
      Spine degeneration in a murine model of chronic human tobacco smokers.
      • Nasto L.A.
      • Wang D.
      • Robinson A.R.
      • Clauson C.L.
      • Ngo K.
      • Dong Q.
      • et al.
      Genotoxic stress accelerates age-associated degenerative changes in intervertebral discs.
      , and in rat models for diabetes
      • Adler J.H.
      • Schoenbaum M.
      • Silberberg R.
      Early onset of disk degeneration and spondylosis in sand rats (Psammomys obesus).
      • Tsai T.-T.
      • Ho N.Y.-J.
      • Lin Y.-T.
      • Lai P.-L.
      • Fu T.-S.
      • Niu C.-C.
      • et al.
      Advanced glycation end products in degenerative nucleus pulposus with diabetes.
      . The exact pathophysiological pathway is not clear, but some information may be gleaned from these experimental models. Disc degeneration in tobacco smoke models is not mediated by genotoxic DNA damage, but by an alteration of cell physiology
      • Nasto L.A.
      • Ngo K.
      • Leme A.S.
      • Robinson A.R.
      • Dong Q.
      • Roughley P.
      • et al.
      Investigating the role of DNA damage in tobacco smoking-induced spine degeneration.
      . This may be caused by the increase of the nitric oxide concentration in the blood, which reduces proteoglycan synthesis
      • Liu G.Z.
      • Ishihara H.
      • Osada R.
      • Kimura T.
      • Tsuji H.
      Nitric oxide mediates the change of proteoglycan synthesis in the human lumbar intervertebral disc in response to hydrostatic pressure.
      . In diabetes models, hyperglycaemia could play a role, either by a direct effect on nucleus cells
      • Won H.-Y.
      • Park J.-B.
      • Park E.-Y.
      • Riew K.D.
      Effect of hyperglycemia on apoptosis of notochordal cells and intervertebral disc degeneration in diabetic rats.
      • Park E.-Y.
      • Park J.-B.
      Dose- and time-dependent effect of high glucose concentration on viability of notochordal cells and expression of matrix degrading and fibrotic enzymes.
      , glycation reactions with aggrecan
      • Roughley P.J.
      • Geng Y.
      • Mort J.S.
      The non-aggregated aggrecan in the human intervertebral disc can arise by a non-proteolytic mechanism.
      , or by the increase of the osmotic value of the blood. However, in both models a biomechanical effect cannot be excluded. In smoke models, the vertebral bodies show a marked increase in porosity, which reduces the structural integrity. In diabetes models, the overweight may induce overloading. Again, it could also be the negative effect on the microcirculation that both smoking and diabetes mellitus have in humans; however, to our knowledge, the effect of smoking or diabetes on endplate microcirculation has not yet been investigated in animal models.
      Evidence for induction of intervertebral disc degeneration through a catabolic shift in cells is not well established in animal models, but there is evidence from IL-1-inhibitor knock-out mice (IL-1rn−/−) that raised levels of IL-1β coincide with intervertebral disc degeneration after 55 days
      • Phillips K.L.E.
      • Jordan-Mahy N.
      • Nicklin M.J.H.
      • Le Maitre C.L.
      Interleukin-1 receptor antagonist deficient mice provide insights into pathogenesis of human intervertebral disc degeneration.
      . Ex vivo, injection of MMP-3, ADAM-TS4 or HTRA-1 showed little effect on catabolic gene expression after 8 days
      • Furtwängler T.
      • Chan S.C.W.
      • Bahrenberg G.
      • Richards P.J.
      • Gantenbein-Ritter B.
      Assessment of the matrix degenerative effects of MMP-3, ADAMTS-4, and HTRA1, injected into a bovine intervertebral disc organ culture model.
      ; however, TNFα addition to the culture medium has been shown to have a persistent catabolic effect on disc cells up to 21 days
      • Purmessur D.
      • Walter B.A.
      • Roughley P.J.
      • Laudier D.M.
      • Hecht A.C.
      • Iatridis J.
      A role for TNFα in intervertebral disc degeneration: a non-recoverable catabolic shift.
      . Infectious processes that induce intervertebral disc degeneration have to our knowledge not been investigated in animal models.

      Extracellular matrix: induction of degeneration

      Herniation of the nucleus
      • Lama P.
      • Le Maitre C.L.
      • Dolan P.
      • Tarlton J.F.
      • Harding I.J.
      • Adams M.A.
      Do intervertebral discs degenerate before they herniate, or after?.
      , puncture of the annulus
      • Carragee E.J.
      • Don A.S.
      • Hurwitz E.L.
      • Cuellar J.M.
      • Carrino J.A.
      • Carrino J.
      • et al.
      2009 ISSLS prize winner: does discography cause accelerated progression of degeneration changes in the lumbar disc: a ten-year matched cohort study.
      , or endplate fracture
      • van Dieën J.H.
      • Weinans H.
      • Toussaint H.M.
      Fractures of the lumbar vertebral endplate in the etiology of low back pain: a hypothesis on the causative role of spinal compression in a specific low back pain.
      • Dudli S.
      • Ferguson S.J.
      • Haschtmann D.
      Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury.
      are associated with the long-term risk of disc degeneration in humans. This damage can be induced through a single traumatic overload
      • Dudli S.
      • Ferguson S.J.
      • Haschtmann D.
      Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury.
      • Alkhatib B.
      • Rosenzweig D.H.
      • Krock E.
      • Roughley P.J.
      • Beckman L.
      • Steffen T.
      • et al.
      Acute mechanical injury of the human intervertebral disc: link to degeneration and pain.
      , which can damage the extracellular matrix, both macroscopically
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Lama P.
      • Le Maitre C.L.
      • Dolan P.
      • Tarlton J.F.
      • Harding I.J.
      • Adams M.A.
      Do intervertebral discs degenerate before they herniate, or after?.
      and microscopically
      • Yoganandan N.
      • Larson S.J.
      • Pintar F.A.
      • Gallagher M.
      • Reinartz J.
      • Droese K.
      Intravertebral pressure changes caused by spinal microtrauma.
      . This results in a loss of intradiscal pressure
      • Iatridis J.C.
      • Weidenbaum M.
      • Setton L.A.
      • Mow V.C.
      Is the nucleus pulposus a solid or a fluid? Mechanical behaviors of the nucleus pulposus of the human intervertebral disc.
      • Dudli S.
      • Ferguson S.J.
      • Haschtmann D.
      Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury.
      • Holm S.
      • Holm A.K.
      • Ekström L.
      • Karladani A.
      • Hansson T.
      Experimental disc degeneration due to endplate injury.
      , and significantly elevated levels of interleukin (IL)-5, IL-6, IL-7, IL-8, MCP-2, GROα, MIG and NGF
      • Dudli S.
      • Ferguson S.J.
      • Haschtmann D.
      Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury.
      • Alkhatib B.
      • Rosenzweig D.H.
      • Krock E.
      • Roughley P.J.
      • Beckman L.
      • Steffen T.
      • et al.
      Acute mechanical injury of the human intervertebral disc: link to degeneration and pain.
      . Interestingly, it appears that the damage to the matrix, either endplate or annulus, is essential for developing intervertebral disc degeneration, rather than simply the absorption of a distinct amount of energy
      • Dudli S.
      • Haschtmann D.
      • Ferguson S.J.
      Fracture of the vertebral endplates, but not equienergetic impact load, promotes disc degeneration in vitro.
      . The induction of degeneration then occurs by decompression of the nucleus
      • Iatridis J.C.
      • Weidenbaum M.
      • Setton L.A.
      • Mow V.C.
      Is the nucleus pulposus a solid or a fluid? Mechanical behaviors of the nucleus pulposus of the human intervertebral disc.
      • Dudli S.
      • Ferguson S.J.
      • Haschtmann D.
      Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury.
      • Holm S.
      • Holm A.K.
      • Ekström L.
      • Karladani A.
      • Hansson T.
      Experimental disc degeneration due to endplate injury.
      , exposure of nucleus cells to matrix fragments
      • Quero L.
      • Klawitter M.
      • Schmaus A.
      • Rothley M.
      • Sleeman J.
      • Tiaden A.N.
      • et al.
      Hyaluronic acid fragments enhance the inflammatory and catabolic response in human intervertebral disc cells through modulation of toll-like receptor 2 signalling pathways.
      , response to neurotrophic and angiotrophic factors
      • Binch A.
      • Cole A.A.
      • Breakwell L.M.
      • Michael A.
      • Chiverton N.
      • Cross A.K.
      • et al.
      Expression and regulation of neurotrophic and angiogenic factors during human intervertebral disc degeneration.
      , or a combination thereof. This illustrates that within the domain of extracellular matrix there are different pathways into the degenerative circle
      • Adams M.A.
      • Dolan P.
      Intervertebral disc degeneration: evidence for two distinct phenotypes.
      , which appear to depend upon decompression and exposure of the nucleus
      • Adams M.A.
      • Freeman B.J.
      • Morrison H.P.
      • Nelson I.W.
      • Dolan P.
      Mechanical initiation of intervertebral disc degeneration.
      • Dudli S.
      • Ferguson S.J.
      • Haschtmann D.
      Severity and pattern of post-traumatic intervertebral disc degeneration depend on the type of injury.
      .
      In animal models, damage to the extracellular matrix is the most commonly used method of induction of intervertebral disc degeneration. Whether the damage is done by chemonucleolysis
      • Fry T.R.
      • Eurell J.C.
      • Johnson A.L.
      • Brown M.D.
      • Losonsky J.M.
      • Schaeffer D.J.
      Radiographic and histologic effects of chondroitinase ABC on normal canine lumbar intervertebral disc.
      • Norcross J.P.
      • Lester G.E.
      • Weinhold P.
      • Dahners L.E.
      An in vivo model of degenerative disc disease.
      • Hoogendoorn R.J.
      • Wuisman P.I.
      • Smit T.H.
      • Everts V.E.
      • Helder M.N.
      Experimental intervertebral disc degeneration induced by chondroitinase ABC in the goat..
      • Sasaki M.
      • Takahashi T.
      • Miyahara K.
      • Hirose aT.
      Effects of chondroitinase ABC on intradiscal pressure in sheep: an in vivo study.
      , annulus puncture
      • Masuda K.
      • Aota Y.
      • Muehleman C.
      • Imai Y.
      • Okuma M.
      • Thonar E.J.
      • et al.
      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.
      • Zhang H.
      • La Marca F.
      • Hollister S.J.
      • Goldstein S.A.
      • Lin C.-Y.
      Developing consistently reproducible intervertebral disc degeneration at rat caudal spine by using needle puncture.
      • Han B.
      • Zhu K.
      • Li F.-C.
      • Xiao Y.-X.
      • Feng J.
      • Shi Z.-L.
      • et al.
      A simple disc degeneration model induced by percutaneous needle puncture in the rat tail.
      • Kong M.H.
      • Do D.H.
      • Miyazaki M.
      • Wei F.
      • Yoon S.
      • Wang J.C.
      Rabbit model for in vivo study of intervertebral disc degeneration and regeneration.
      or endplate perforation
      • Holm S.
      • Holm A.K.
      • Ekström L.
      • Karladani A.
      • Hansson T.
      Experimental disc degeneration due to endplate injury.
      • Vadalà G.
      • De Strobel F.
      • Bernardini M.
      • Denaro L.
      • D'Avella D.
      • Denaro V.
      The transpedicular approach for the study of intervertebral disc regeneration strategies: in vivo characterization.
      , progressive degenerative disc degeneration is seen. Unfortunately, a comparison of the chronological order of cellular and biomechanical changes between these different methods of degeneration induction has not been performed. However, it has been established that pressure drop
      • Holm S.
      • Ekström L.
      • Holm A.K.
      • Hansson T.
      Intradiscal pressure in the degenerated porcine intervertebral disc.
      and the expression of catabolic agents
      • Dudli S.
      • Haschtmann D.
      • Ferguson S.J.
      Fracture of the vertebral endplates, but not equienergetic impact load, promotes disc degeneration in vitro.
      • Haschtmann D.
      • Stoyanov J.V.
      • Gédet P.
      • Ferguson S.J.
      Vertebral endplate trauma induces disc cell apoptosis and promotes organ degeneration in vitro.
      • Holm S.
      • Mackiewicz Z.
      • Holm A.K.
      • Konttinen Y.T.
      • Kouri V.-P.
      • Indahl A.
      • et al.
      Pro-inflammatory, pleiotropic, and anti-inflammatory TNF-alpha, IL-6, and IL-10 in experimental porcine intervertebral disk degeneration.
      occur both ex vivo and in vivo. Interestingly, it has been shown that disc stress distributions in the IVD are influenced more by damage to the endplate than by injuries to the outer annulus
      • Przybyla A.
      • Pollintine P.
      • Bedzinski R.
      • Adams M.A.
      Outer annulus tears have less effect than endplate fracture on stress distributions inside intervertebral discs: relevance to disc degeneration.
      , but again, direct comparison of the differences in cellular changes between these two pathways has not yet been performed.
      In summary, both in human epidemiology and in animal models there is evidence for numerous pathways towards progressive disc degeneration. This is important because it illustrates why intervertebral disc degeneration has been called multi-factorial. The degenerative circle can explain most of the common risk factors for intervertebral disc disease, and the progressive nature of degenerative disc disease.

      Discussion

      In this paper we propose a model for intervertebral disc degeneration: the degenerative circle. This model is based on the most prominent alterations that occur in the nucleus pulposus in intervertebral disc disease, and consists of a positive feedback loop involving cells, extracellular matrix, and biomechanics. Additionally, this paper aims to provide insights into the pathways into the degenerative circle based on human epidemiology and animal models for intervertebral disc degeneration.
      Both Adams et al.
      • Adams M.A.
      • Dolan P.
      • McNally D.S.
      The internal mechanical functioning of intervertebral discs and articular cartilage, and its relevance to matrix biology.
      and Colombini et al.
      • Colombini A.
      • Lombardi G.
      • Corsi M.M.
      • Banfi G.
      Pathophysiology of the human intervertebral disc.
      have proposed pathophysiological models for intervertebral disc degeneration that include some of the relations of the degenerative circle. The model of Adams et al. focuses on structural damage to the extracellular matrix and is progressive due to a frustrated cellular healing response, mainly because of a drop of intradiscal pressure. Their model thus differs in two fundamental ways: firstly, it only allows for disc degeneration to occur upon damage to the extracellular matrix. Secondly, in their model, mechanobiological cues are limited to a decrease in intradiscal pressure, and do not include an increase in shear stresses. However, this seems crucial for the breakdown of aggrecan, and the transdifferentiation to collagen type 1 producing cells. The model of Colombini et al. regards chronic abnormal load as the main cause of intervertebral disc degeneration; they state that this will lead to a catabolic cell response, and consecutively an altered matrix. There are similarities with the degenerative circle; however, again their model differs in crucial ways: their model does not allow for aberrant cell physiology or damage to the extracellular matrix to induce disc degeneration, nor does it elaborate on how the catabolic cell response is induced. Furthermore, their model does not stress the progressive nature through a positive feedback loop. The degenerative circle thus presents a more complete view of intervertebral disc degeneration as it allows for multiple ways of induction of intervertebral disc degeneration, illustrates the progressive nature through a positive feedback loop, and is the first to elaborate on the mechanobiological cues that play a role in intervertebral disc degeneration.
      The degenerative circle is a simple model. It provides a practical tool for clarifying the complex interactions of intervertebral disc disease to patients, medical students, and clinicians. Additionally, this model stresses the importance of the interaction between cells, extracellular matrix and biomechanical behaviour, and illustrates that all are important in intervertebral disc degeneration. This is essential because all three domains and their interactions need to be considered if we want to reverse or halt the degenerative process. However, the simple elegance of the degenerative circle has intrinsic shortcomings as it contains some oversimplifications.
      Weaknesses in the proposed model include a lack of other feedback mechanisms in intervertebral disc physiology. Clearly, besides a pathway through biomechanical changes, there is an also a direct feedback loop from the extracellular matrix to the cells. This is mainly dominated by the osmotic charge of the proteoglycans. Numerous other mechanisms (e.g., endplate sclerosis
      • Roberts S.
      • Urban J.P.
      • Evans H.
      • Eisenstein S.M.
      Transport properties of the human cartilage endplate in relation to its composition and calcification..
      , the effect of loading on nutrition
      • Arun R.
      • Freeman B.J.C.
      • Scammell B.E.
      • McNally D.S.
      • Cox E.
      • Gowland P.
      2009 ISSLS Prize Winner: what influence does sustained mechanical load have on diffusion in the human intervertebral disc?: an in vivo study using serial postcontrast magnetic resonance imaging.
      , low-grade infection
      • Alpantaki K.
      • Katonis P.
      • Hadjipavlou A.G.
      • Spandidos D.A.
      • Sourvinos G.
      Herpes virus infection can cause intervertebral disc degeneration: a causal relationship?.
      , toll-like receptor stimulation