What is intervertebral disc degeneration, and what causes it?
ABSTRACT STUDY DESIGN: Review and reinterpretation of existing literature. OBJECTIVE: To suggest how intervertebral disc degeneration might be distinguished from the physiologic processes of growth, aging, healing, and adaptive remodeling. SUMMARY OF BACKGROUND DATA: The research literature concerning disc degeneration is particularly diverse, and there are no accepted definitions to guide biomedical research, or medicolegal practice. DEFINITIONS: The process of disc degeneration is an aberrant, cell-mediated response to progressive structural failure. A degenerate disc is one with structural failure combined with accelerated or advanced signs of aging. Early degenerative changes should refer to accelerated age-related changes in a structurally intact disc. Degenerative disc disease should be applied to a degenerate disc that is also painful. JUSTIFICATION: Structural defects such as endplate fracture, radial fissures, and herniation are easily detected, unambiguous markers of impaired disc function. They are not inevitable with age and are more closely related to pain than any other feature of aging discs. Structural failure is irreversible because adult discs have limited healing potential. It also progresses by physical and biologic mechanisms, and, therefore, is a suitable marker for a degenerative process. Biologic progression occurs because structural failure uncouples the local mechanical environment of disc cells from the overall loading of the disc, so that disc cell responses can be inappropriate or "aberrant." Animal models confirm that cell-mediated changes always follow structural failure caused by trauma. This definition of disc degeneration simplifies the issue of causality: excessive mechanical loading disrupts a disc's structure and precipitates a cascade of cell-mediated responses, leading to further disruption. Underlying causes of disc degeneration include genetic inheritance, age, inadequate metabolite transport, and loading history, all of which can weaken discs to such an extent that structural failure occurs during the activities of daily living. The other closely related definitions help to distinguish between degenerate and injured discs, and between discs that are and are not painful.
- [show abstract] [hide abstract]
ABSTRACT: A literature review. To synthesize the scientific literature on the prevalence of lumbar disc degeneration and factors associated with its occurrence, including genetic influences. A literature review was conducted of the prevalence of disc degeneration. Studies of the etiology of disc degeneration were summarized, with particular attention given to studies of genetic influences. There are extreme variations in the reported prevalence of specific degenerative findings of the lumbar spine among studies, which cannot be explained entirely by age or other identifiable risk factors (e.g., prevalence figures for disc narrowing varied from 3% to 56%). It is likely that these variations are due, in great part, to inconsistencies in case definitions and measurements, which are impeding epidemiologic research on disc degeneration. Research conducted over the past decade has led to a dramatic shift in the understanding of disc degeneration and its etiology. Previously, heavy physical loading was the main suspected risk factor for disc degeneration. However, results of exposure-discordant monozygotic and classic twin studies suggest that physical loading specific to occupation and sport has a relatively minor role in disc degeneration, beyond that of upright postures and routine activities of daily living. Recent research indicates that heredity has a dominant role in disc degeneration, explaining 74% of the variance in adult populations studied to date. Since 1998, genetic influences have been confirmed by the identification of several gene forms associated with disc degeneration.Spine 01/2005; 29(23):2679-90. · 2.16 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Aggrecan, a large aggregating proteoglycan, is one of the major structural components of cartilage. Its core protein contains three glubular domains and two glycosaminoglycan-attachment domains. These domains play various roles to maintain cartilage structure and function. An N-terminal globular domain binds hyaluronan and link protein to form huge aggregates. The chondroitin sulfate (CS) chains attach to the CS domain and provide a hydrated, viscous gel that absorbs compressive load. Two autosomal recessive chondrodysplasias, cartilage matrix deficiency (cmd) in mice and nanomelia in chicken are both caused by aggrecan gene mutations. Cmd homozygotes die shortly after birth, while the heterozygotes are born normal. However, cmd heterozygotes develop late onset of spinal disorder, which suggests aggrecan as a candidate gene predisposing individuals to spinal problems. Nanomelia is a useful model to elucidate intracellular trafficking of proteoglycans. Further studies on aggrecan will lead to prophylaxis and treatment of joint destructive diseases such as osteoarthrosis and to elucidation of cartilage development, which is essential for skeletal formation.Journal of Biochemistry 11/1998; 124(4):687-93. · 2.72 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: A review of the literature on disc nutrition. To summarize the information on disc nutrition in relation to disc degeneration. The disc is avascular, and the disc cells depend on diffusion from blood vessels at the disc's margins to supply the nutrients essential for cellular activity and viability and to remove metabolic wastes such as lactic acid. The nutrient supply can fail due to changes in blood supply, sclerosis of the subchondral bone or endplate calcification, all of which can block transport from blood supply to the disc or due to changes in cellular demand. A review of the studies on disc blood supply, solute transport, studies of solute transport in animal and human disc in vitro, and of theoretical modeling studies that have examined factors affecting disc nutrition. Small nutrients such as oxygen and glucose are supplied to the disc's cells virtually entirely by diffusion; convective transport, arising from load-induced fluid movement in and out of the disc, has virtually no direct influence on transport of these nutrients. Consequently, there are steep concentration gradients of oxygen, glucose, and lactic acid across the disc; oxygen and glucose concentrations are lowest in the center of the nucleus where lactic acid concentrations are greatest. The actual levels of concentration depend on the balance between diffusive transport and cellular demand and can fall to critical levels if the endplate calcifies or nutritional demand increases. Loss of nutrient supply can lead to cell death, loss of matrix production, and increase in matrix degradation and hence to disc degeneration.Spine 01/2005; 29(23):2700-9. · 2.16 Impact Factor
SPINE Volume 31, Number 18, pp 2151–2161
©2006, Lippincott Williams & Wilkins, Inc.
What is Intervertebral Disc Degeneration, and What
Michael A. Adams, PhD,* and Peter J. Roughley, PhD†
Study Design. Review and reinterpretation of existing
Objective. To suggest how intervertebral disc degener-
ation might be distinguished from the physiologic pro-
cesses of growth, aging, healing, and adaptive remodeling.
Summary of Background Data. The research literature
concerning disc degeneration is particularly diverse, and
there are no accepted definitions to guide biomedical
research, or medicolegal practice.
Definitions. The process of disc degeneration is an ab-
errant, cell-mediated response to progressive structural fail-
ure. A degenerate disc is one with structural failure com-
bined with accelerated or advanced signs of aging. Early
degenerative changes should refer to accelerated age-re-
lated changes in a structurally intact disc. Degenerative disc
disease should be applied to a degenerate disc that is also
Justification. Structural defects such as endplate frac-
ture, radial fissures, and herniation are easily detected,
unambiguous markers of impaired disc function. They are
not inevitable with age and are more closely related to
pain than any other feature of aging discs. Structural
failure is irreversible because adult discs have limited
healing potential. It also progresses by physical and bio-
logic mechanisms, and, therefore, is a suitable marker for
a degenerative process. Biologic progression occurs be-
cause structural failure uncouples the local mechanical
environment of disc cells from the overall loading of the
disc, so that disc cell responses can be inappropriate or
“aberrant.” Animal models confirm that cell-mediated
changes always follow structural failure caused by trauma.
This definition of disc degeneration simplifies the issue of
causality: excessive mechanical loading disrupts a disc’s
structure and precipitates a cascade of cell-mediated re-
sponses, leading to further disruption. Underlying causes of
disc degeneration include genetic inheritance, age, inade-
quate metabolite transport, and loading history, all of which
can weaken discs to such an extent that structural failure
occurs during the activities of daily living. The other closely
related definitions help to distinguish between degenerate
and injured discs, and between discs that are and are not
Key words: intervertebral disc, degeneration, defini-
tion, etiology, review. Spine 2006;31:2151–2161
molecular biology, and the scientific literature on the
subject is particularly diverse. Perhaps as a result of this,
there is no consensus on what “disc degeneration” actu-
ally is or how it should be distinguished from the physi-
ologic processes of growth, aging, healing, and adaptive
remodeling. We suggest that a precise definition of disc
which degenerative features are most likely to influence
patients’ prognosis and which are the best targets for
therapeutic interventions. It would help epidemiologists
identify risk factors for the disease1and suggest im-
proved strategies for prevention. In addition, medicole-
gal experts would be better able to distinguish between a
disease process and normal “constitutional” changes.
Recently, the relevant research literature has been
thoroughly reviewed and summarized,2although no def-
initions were suggested. At a subsequent symposium in
Davos, Switzerland, in 2005, there was widespread agree-
ment that a definition would be beneficial but no agree-
ment on how it should be phrased.3We suggest that the
time is right to introduce a working definition of disc
degeneration, one which will stimulate further discus-
sion and lead to a formulation that will satisfy most
researchers working in the field.
The purpose of the present article is to propose and jus-
tify a working definition of intervertebral disc degenera-
tion, and show how it facilitates interpretation of the di-
concerning intervertebral disc functional anatomy, metab-
olism, aging, structural failure, and pain. This review is
followed by an account of disc degeneration as suggested
by animal models and epidemiology. Finally, 2 “interpre-
tation” sections consider what disc degeneration is and
what causes it.
Disc Functional Anatomy
Intervertebral discs are pads of fibrocartilage that resist
spinal compression while permitting limited movements.
They spread loading evenly on the vertebral bodies, even
when the spine is flexed or extended. Individual lamellae
of the anulus fibrosus consist primarily of collagen type I
fibers passing obliquely between vertebral bodies, with
orientation of the fibers being reversed in successive la-
mellae (Figure 1). The nucleus pulposus consists of a
proteoglycan and water gel held together loosely by an
irregular network of fine collagen type II and elastin fi-
bers. The major proteoglycan of the disc is aggrecan,5,6
From the *Department of Anatomy, University of Bristol, Bristol,
United Kingdom, and †Shriners Hospital, Montreal, Canada.
Acknowledgment date: August 4, 2005. First revision date: November
7, 2005. Acceptance date: November 7, 2005.
The manuscript submitted does not contain information about medical
Federal funds were received in support of this work. No benefits in any
form have been or will be received from a commercial party related
directly or indirectly to the subject of this manuscript.
Address correspondence and reprint requests to Michael A. Adams,
PhD, Department of Anatomy, University of Bristol, Southwell Street,
Bristol BS2 8EJ, United Kingdom; E-mail: M.A.Adams@bris.ac.uk
which, because of its high anionic glycosaminoglycan
content (i.e., chondroitin sulfate and keratan sulfate),
provides the osmotic properties needed to resist com-
pression (Figure 2).
The internal mechanical functioning of an interverte-
bral disc can be studied by pulling a miniature pressure
transducer through it. A young healthy disc behaves like
a water bed, with the high water content of the nucleus
and inner anulus enabling the tissue to act like a fluid
(Figure 3A). Only the outermost anulus acts as a tensile
“skin” to restrain the nucleus. With increasing age, disc
water content decreases, especially in the nucleus, and
most of the anulus then acts like a fibrous solid to resist
compression directly (Figure 3B). In physically disrupted
discs (Figure 3C), regions of fibrous tissue resist mechan-
ical loading in a haphazard manner, and the hydrostatic
nucleus is reduced or absent.
Cells in the anulus are elongated parallel to the collagen
fibers, rather like fibroblasts. Cells in the nucleus are
initially notochordal but are gradually replaced during
childhood by rounded cells resembling the chondrocytes
of articular cartilage. Anulus cells synthesize mostly col-
lagen type I in response to deformation, whereas nucleus
cells respond to hydrostatic pressure by synthesizing
mostly proteoglycans and fine collagen type II fibrils.
Cell density declines during growth,7and in the adult is
has been reviewed recently.8,9
outmost layers of the anulus. Metabolite transport is by
diffusion, which is important for small molecules, and by
bulk fluid flow, which is important for large mole-
cules.8,10Transport routes are shown in Figure 4. Low
oxygen tension in the center of a disc leads to anaerobic
metabolism, resulting in a high concentration of lactic
acid and low pH.8In vitro experiments show that a
chronic lack of oxygen causes nucleus cells to become
quiescent, whereas a chronic lack of glucose can kill
them.12Deficiencies in metabolite transport appear to
limit both the density and metabolic activity of disc
cells.8As a result, discs have only a limited ability to
recover from any metabolic or mechanical injury. End-
plate permeability and, therefore, disc metabolite trans-
port normally decrease during growth and aging, and yet
increase in the presence of disc degeneration and follow-
ing endplate damage.13This is one essential difference
between aging and degeneration.
Growth and Adaptive Remodeling
Disc cells synthesize their matrix and break down exist-
ing matrix by producing and activating degradative en-
“a disintegrin and metalloproteinase” (ADAMS).14–20
Molecular markers of matrix turnover are naturally
most plentiful during growth but usually decline there-
after.21The major structural changes to the disc occur
Figure 1. Intervertebral disc structure and function. Upper, spinal
compression (C) generates a hydrostatic pressure (P) in the nucleus,
and tensile stresses (T) in the anulus. Lower, Lamellae of the anulus
with oblique collagen fibers in alternating directions (approximately,
? ? 30°). Typical values are given of the number of lamellae in the
anulus and the number of collagen fiber bundles in a lamella. Re-
printed with permission from Churchill Livingstone; 2002.4
Figure 2. The role of aggrecan and collagen in the ability of disc
to resist compression. The nucleus pulposus is depicted as con-
taining proteoglycan aggregates entrapped in a collagen fiber
network. The proteoglycan aggregates are depicted as a central
hyaluronan molecule (dashed line) substituted with aggrecan mol-
ecules possessing a central core protein (open line) and sulfated
glycosaminoglycan side chains (solid lines). The hydration prop-
erties of the glycosaminoglycan chains of aggrecan cause the
tissue to swell until an equilibrium is reached, in which the swell-
ing potential is balanced by tensile forces in the collagen network.
Compressive loading of the spine forces some water from the disc
effectively increasing the aggrecan concentration and its swelling
potential, and resisting further compression. On removal of the
compressive load, disc height is restored as water is drawn back
into the tissue to restore the original equilibrium conditions. Any
parameter that decreases proteoglycan concentration or weakens
the collagen network will be detrimental to disc function.
2152Spine•Volume 31•Number 18•2006
in consistency from a translucent fluid to a soft amorphous
tissue,22caused mainly by an increase in collagen content.
The proteoglycan content of the disc is maximal in the
young adult and declines thereafter,21presumably because
of proteolysis. Disc cells appear to adapt the properties of
their matrix to suit prevailing mechanical demands, al-
though the low cell density and lack of a blood supply
ensure that changes are not as rapid or pronounced as in
adjacent vertebrae.23Adaptive remodeling probably con-
tributes to the large variation in compressive strength of
adult discs, which ranges from 2.8 to 13.0 kN when they
are tested in a manner that causes failure in the disc rather
than the adjacent vertebra.24
Injured discs show increased levels of catabolic cyto-
kines, increased MMP activity,21,25and scar forma-
tion,26especially in the vicinity of anular tears.26,27They
also show evidence of renewed matrix turnover21,28and
a more variable range of collagen fibril diameters.29
However, gross injuries to a disc never fully heal. Scalpel
cuts in the outer anulus fill with granulation tissue, with
only the outer few millimeters being bridged by scar tis-
sue.30,31Anular tears are not remodeled as in bone, pre-
sumably because the sparse cell population is unable to
and replace them with new.32Collagen turnover time in
articular cartilage is approximately 100 years33and could
be even longer in the disc. Proteoglycan turnover is
faster, possibly 20 years,32and some regeneration of nu-
cleus pulposus is possible in young animals.34Injuries
that affect the inner anulus or endplate decompress the
nucleus,35and healing processes are then overtaken by
severe degenerative changes.31
Proteoglycan fragmentation starts during childhood,36
and with increasing age, the overall proteoglycan and
water content of the disc decreases, especially in the nu-
cleus.21There is a corresponding increase in collagen
content, a tendency for fine type II collagen fibrils in the
inner anulus to be replaced by type I fibers as the anulus
encroaches on the nucleus, and for type I fibers through-
out the disc to become coarser. Loss of proteoglycan
fragments from the disc is a slow process owing to the
entrapment of the nucleus by the fibrous anulus and the
cartilage endplates of the vertebrae.37As long as the pro-
teoglycan fragments remain entrapped in the disc, they
can fulfill a functional role similar to that of the intact
proteoglycan. Reduced matrix turnover in older discs en-
ables collagen molecules and fibrils to become increasingly
cross-linked with each other, and existing cross-links be-
come more stable.28In addition, reactions between colla-
gen and glucose lead to “nonenzymatic glycation” (extra
Figure 3. “Stress profiles” showing the distribution of compressive
stress across the midsagittal diameter of lumbar intervertebral discs
subjected to 2 kN of compression. Vertical and horizontal “stresses”
1” disc. (B) Middle-aged “Grade 2” disc, showing a stress concen-
tration of magnitude “h” in the posterior anulus. The hydrostatic
functional nucleus lies between the 2 vertical dashed lines. (C) De-
generated “Grade 3” disc with multiple stress concentrations in the
anulus (arrow). Compare with Figure 6. Reprinted with permission
from Churchill Livingstone; 2002.4
Figure 4. Organization of the vertebral endplate. The vertebral end-
plate consists of hyaline cartilage weakly bonded to the perforated
cortical bone of the vertebral body, and collagen fibers of the anulus
and nucleus. Arrows indicate routes for nutrient transport from sur-
rounding blood vessels into the central regions of the disc. Adapted
from J Orthop Res 1993;11:747–57.11
2153What is Disc Degeneration?•Adams and Roughley
cross-links that give old discs their characteristic yellow-
brown appearance).38Increased cross-linking inhibits
matrix turnover and repair in old discs, encouraging the
retention of damaged macromolecules32and probably
leading to reduced tissue strength.
endplate decreases, and microstructural clefts and tears
become common by the age of 15 years, especially in the
nucleus and endplate.39Cell density decreases through-
out growth,7and from skeletal maturity onward, there is
a steadily increasing incidence of structural defects ex-
tending into the anulus.26The nucleus pulposus tends to
condense into several fibrous lumps, separated from each
other and from the cartilage endplate by softer material.40
Sequential histologic changes across 9 decades have re-
cently been classified.39Generally, these changes affect the
different spinal levels are affected to a similar extent.
Matrix synthesis decreases steadily throughout life but
sometimes increases again in old and severely disrupted
discs.21Reduced synthesis is partly attributable to de-
creased cell density, although proteoglycan synthesis
rates per cell also decrease.41Cell proliferation can occur
locally in association with fissures and increased MMP
activity.26,27Age-related changes in the types of collag-
ens and MMPs synthesized suggest that cell phenotype
can change,27possibly in response to altered matrix
stress distributions (Figure 3).
With increasing age, the hydrostatic nucleus becomes
smaller and decompressed, and so more of the compres-
fulfill this functional demand, the inner anulus of the
tent.21However, with increasing age, the proteoglycan
content decreases, and the anulus becomes stiffer and
weaker.43Disc height does not show a major decrease
with age,44although degenerative changes can cause the
anulus to collapse in some old discs (see later).
Disc Structural Failure
There are 3 types of tears that can be distinguished: cir-
cumferential tears or “delaminations,” peripheral rim
tears, and radial fissures (Figure 5). They become in-
creasingly common after the age of 10 years,39especially
in the lower lumbar spine, and reach a peak in middle
age.45Circumferential tears may represent the effects of
interlaminar shear stresses,46possibly occurring from
compressive stress concentrations in older discs (Figure
3). Peripheral rim tears are more frequent in the anterior
they are related to trauma. Radial fissures progress out-
ward from the nucleus, usually posteriorly or posterolater-
ally,47and this process can be simulated in cadaveric discs
by cyclic loading in bending and compression.4Radial fis-
sures are associated with nucleus “degeneration,”47,49
but it is not clear which comes first. The 3 types of
anulus tear probably evolve independently of age and
When radial fissures allow gross migration of nucleus
relative to anulus, to the extent that the disc periphery is
affected, then the disc can be said to be herniated, or
prolapsed. Depending on the extent of nucleus migra-
tion, the disc herniation may result in protrusion, extru-
sion, or sequestration of the nuclear material. Disc pro-
lapse can be simulated in cadaveric discs by combined
loading in bending and compression, with either one
component exceeding physiologic limits,24,35or as a re-
sult of intense repetitive loading.51,52Mechanically in-
duced prolapse (Figure 6E) occurs most readily in discs
aged 30–40 years,24,53which presumably still have a
fluid nucleus and an anulus starting to become weakened
by age. “Severely degenerated” discs do not prolapse in
the laboratory, presumably because the nucleus is no
longer able to exert a hydrostatic pressure to tension the
anulus. In living people, prolapsed disc tissue consists
primarily of nucleus pulposus displaced down a radial
Endplate Damage and Schmorl Nodes
Vertebral endplates (Figure 4) are the spine’s “weak
link” in compression, and accumulating trabecular mi-
crodamage55probably explains why the nucleus increas-
ingly bulges into the vertebral bodies in later life.56End-
plate damage immediately decompresses the adjacent
nucleus and transfers load onto the anulus, causing it to
Figure 5. Three common types of anulus tears. A, Circumferential
clefts or delamination. B, Radial fissure. C, Peripheral rim lesion.
Disrupted tissue is shown in black, and nucleus pulposus is shaded.
Images are in the transverse plane (left) and sagittal plane (right).
Reprinted with permission from Churchill Livingstone; 2002.4
2154Spine•Volume 31•Number 18•2006
bulge into the nucleus cavity (Figure 6C).35,57If nucleus
pulposus herniates through a damaged endplate, then
subsequent calcification can create a “Schmorl’s node.”
Internal Disc Disruption58
Collapse of the inner anulus into the nucleus is a common
feature of elderly discs (Figures 6C, D), with the anterior
anulus being affected more than the posterior.59,60It could
be caused by nucleus decompression following endplate
fracture, as described previously. In many elderly discs, the
cartilage endplate becomes detached from underlying
bone,60presumably because the high internal pressure that
presses it against the bone in young discs has been lost.
Disc Narrowing, Radial Bulging, and
These 3 features are closely associated with one another
and with the term “spondylosis” (Figure 7). With in-
creasing age, the nucleus tends to bulge into the vertebral
bodies. Nucleus pressure is reduced,61,62and increased
vertical loading of the anulus61causes it to bulge radially
outward,63and sometimes inward. Severe changes are
accompanied by a marked loss of nucleus pressure62and
collapse of anulus height (Figure 6D). In effect, the disc
behaves like a “flat tire.”63It is anulus height that deter-
mines the separation of adjacent neural arches, and anu-
lus collapse/bulging in old discs can lead to more than
50% of the compressive force on the lumbar spine being
resisted by the neural arch.64This effect probably ex-
plains why narrowed discs are associated with osteoar-
thritis in the apophyseal joints and with osteophytes
(Figure 7) around the margins of the vertebral bodies.65
the anterior and lateral regions are supplied by autonomic
nerves.66Nociceptive nerve fibers normally penetrate only
the outermost 1–3 mm of anulus67,68but have been re-
ported to progress in toward the nucleus in the anterior
regions of painful and severely disrupted discs.67The bony
vertebral endplate has a similar density of innervation.69
Pain provocation studies associate severe back pain
with relatively innocuous mechanical stimulation of the
outer posterior anulus and endplate.70Painful discs are
always structurally disrupted67and show irregular stress
concentrations.71They appear to become sensitized to
mechanical loading, and animal experiments have con-
firmed that contact with nucleus pulposus can lower
Figure 6. Cadaveric lumbar intervertebral discs sectioned in the
midsagittal plane (anterior on left). (A) Young disc (male, 35 years
old). (B) Mature disc (male, 47 years old). (C) Disrupted young disc
(male, 31 years old). Note the endplate damage and inward col-
lapse of the inner anulus. (D) Severely disrupted young disc (male,
31 years old). Note the collapse of disc height. (E) Disc induced to
prolapse in the laboratory (male, 40 years old). Some nucleus
pulposus has herniated through a radial fissure in the posterior
anulus (right). Discs (A–D) correspond to the 4-point scales typi-
cally used to grade “disc degeneration” from macroscopic fea-
tures. Reprinted with permission from Churchill Livingstone; 2002.4
Figure 7. Radiograph of an old cadaveric lumbar spine (anterior on
left). The radiograph depicts how severe disc narrowing can be
associated with vertebral osteophytes, sclerosis of the vertebral
endplates, and selective loss of horizontal trabeculae from the
vertebral body. Reprinted with permission from Churchill Living-
2155 What is Disc Degeneration?•Adams and Roughley
nerve stimulation thresholds in adjacent tissues.72Pain
sensitization is of most functional significance when it
occurs in the outer anulus fibrosus because that is where
the highest stress concentrations are found in “degener-
ated” discs (Figure 3C).
Features of discs most closely associated with pain
include disc prolapse,49disc narrowing,73,74radial fis-
sures,73,75especially when they reach the disc exterior
and “leak,”76and internal disc disruption, including in-
ward collapse of the anulus.77More variably related to
pain are endplate fracture and Schmorl nodes,78and disc
bulging.49,73,78,79Disc signal intensity on magnetic res-
onance imaging (MRI) has little if any relationship to
Disc Degeneration: Animal Models
Animal models provide a reliable guide to biologic pro-
cesses within degenerating discs because they preserve the
complex mechanical and biochemical environment of disc
cells. However, they are less useful for investigating how
the interventions (or genetic defects) may not represent
ing to their increased cell density, improved metabolite
transport, and the presence of notochordal cells in the ma-
ture nucleus.80These differences can result in an increased
propensity for disc repair.
Surgical disruption of the endplate or anulus leads
inexorably to “degenerative” changes throughout the
disc.57,81Perforation of the endplate from the side of the
can loss, and internal disruption of the anulus.57The
anulus disruption model, which simulates a peripheral
rim tear, causes subsequent changes in the nucleus and
endplate,30,81,82and shows that degenerative changes,
unlike aging, need not start in the nucleus. Compressive
loading of rodent tail discs can result in cell death, im-
paired matrix synthesis, and disruption of the anulus and
vertebral body.83–85Compression without immobilization
affects disc cell metabolism and matrix composition but
does not lead to any architectural degenerative changes.86
Injecting cement into the vertebral body to block nutri-
ent transport through the endplate does not lead to disc
degeneration within 1 year.87
The time span for detectable degenerative changes to
occur ranges from 1 week for mice88to many months for
pigs and sheep.57,81For comparison, in human adoles-
cents, it takes several years for disc “degeneration” to
become apparent after endplate injury,89and narrowing
in adult human discs progresses at approximately 3%
Disc Degeneration: Epidemiology
Regardless of which definition is used, disc “degenera-
tion” increases with age and is most common in the
lower lumbar spine.65The highest risk factor is genetic
inheritance, which accounts for approximately 50–70%
of the variability in disc degeneration between identical
twins.1,90It is noteworthy that this 50–70% does not
eration on spinal level, which probably reflects environ-
mental influences.1Individual genes associated with disc
degeneration include those for collagen type IX,91aggre-
can,92vitamin D receptor,93MMP3,94and cartilage in-
termediate layer protein.95The products of these genes
probably affect the strength of skeletal tissues, and their
systemic effects may explain why disc degeneration is
more prevalent in those with osteoarthritis.74Environ-
mental risk factors for disc degeneration include high
and repetitive mechanical loading1,96and smoking ciga-
rettes.97Disc prolapse is closely associated with heavy
lifting,98but not with other features of spinal degenera-
tion or age,65suggesting that prolapse is not an integral
part of the aging process.
Interpretation: What is Disc Degeneration?
The aforementioned evidence shows that many different
influences are at work in old and degenerating discs,
including genetic inheritance, impaired metabolite trans-
port, altered levels of enzyme activity, cell senescence
and death, changes in matrix macromolecules and water
content, structural failure, and neurovascular ingrowth.
Is it possible to use one or more of these processes to
define disc degeneration? To be useful, the definition
should be unambiguous and easy to apply to the discs of
living people. It should be distinguishable from the inev-
itable and physiologic processes of growth, aging, and
adaptive remodeling. It should be clinically relevant in
terms of dysfunction or pain, and it should be consistent
with the normal usage of “declining to a lower or worse
stage of being.”99An unfavorable genetic inheritance is
present from birth, and yet disc degeneration becomes
common only 40 years later, and then only in lower
lumbar discs. This implies that genetic inheritance, in-
cluding polymorphic variations in susceptibility genes, is
only a risk factor for future environmentally triggered
events and does not in itself constitute disc degeneration.
Inadequate metabolite transport appears to be an in-
evitable consequence of growth and probably has little
direct clinical relevance because it mostly affects the nu-
cleus pulposus, which is the region of degenerated discs
that is loaded the least (Figure 3C) and has the fewest
nerve endings. The fact that endplate damage leads to
disc degeneration, even though it enhances metabolite
transport into the disc,13suggests that structural damage
has the decisive influence on the degenerative process.
The animal models of disc degeneration described previ-
ously support this inference. Inadequate nutrition may
ability to respond to increased loading, or injury.
Certain markers of altered cell metabolism, such as
increased cytokine and MMP activity,100,101could be
used as a definition. They are associated with structural
defects in the disc,27but currently available markers are
unable to differentiate degeneration from growth, adap-
2156Spine•Volume 31•Number 18•2006
tive remodeling, and healing. Logically, to suggest that
cytokines or proteinases “cause” disc degeneration is
equivalent to blaming war on soldiers! Cytokines and
proteinases are merely agents of change, rather than
causes. The very complexity of connective tissue metab-
olism suggests that degeneration could occur from a fail-
ure to regulate specific proteinase activities.94,102How-
ever, it could equally be argued that the redundancy
inherent in such a complex system (cells can achieve a
given effect by many different methods) ensures that the
system is very robust.
Aging causes inevitable and progressive changes in disc
collagenous tissues. Biochemical changes influence tissue
can impair disc cell metabolism.103In addition, some ma-
trix changes are detectable in vivo using MRI, manifest-
ing as a “dark disc.”104However, age-related changes in
matrix composition are inevitable, start soon after
birth,36,39and are unrelated to pain.1Age-related reduc-
tions in endplate vascularity and disc cell density7could
simply reflect necessary adaptations to increased me-
chanical loading at the onset of ambulation, and reduced
metabolite transport in a growing disc. The microstruc-
tural clefts and tears that appear increasingly during
growth may possibly lead to more extensive disruption
in later life, but so long as they remain small, they appear
to have little effect on the internal mechanical function of
the disc.61In addition, they affect all spinal levels to a
similar extent, unlike macroscopic changes that occur
mostly between L4 and S1.
Ingrowth of nerves and blood vessels is an important
feature of structurally disrupted discs, and appears to be
directly, though variably, associated with pain.67In-
growth could be facilitated by the loss of hydrostatic
(Figure 3) and that would collapse hollow capillaries.
Reduced proteoglycan content in old and degenerated
discs may also facilitate the ingrowth of nerves and cap-
illaries105because aggrecan can inhibit their growth in
vitro.106,107Whichever mechanism is favored, it is ap-
parent that ingrowth of blood vessels and nerves is too
late an event in disc degeneration to be useful as a defin-
This leaves structural failure as a candidate for defin-
ing disc degeneration. We suggest that certain manifes-
tations of structural failure meet all of the aforemen-
tioned criteria. They are easily detected, unambiguous
markers of impaired disc function that do not occur in-
evitably with increasing age, and that are more closely
related to back pain and sciatica than any other feature
of aging or degenerated discs. Structural failure is per-
manent because adult discs are incapable of repairing
Furthermore, structural failure naturally progresses
by physical and biologic mechanisms and, therefore, is a
suitable marker for a degenerative process. Physically,
damage to one part of a disc increases load-bearing by
adjacent tissue, so the damage is likely to spread. This
principle explains crack propagation in engineering ma-
terials and why peripheral rim tears in animal discs
progress in toward the nucleus.81Similarly, pathologic ra-
dial bulging of a disc progresses because compressive
forces act to collapse the bulging lamellae. Biologic
mechanisms of progression depend on the fact that a
healthy intervertebral disc equalizes pressure within it,
whereas a disrupted disc shows high concentrations of
compressive stress in the anulus, and a decompressed
nucleus (Figures 3C, 8). Reduced nucleus pressure im-
pairs proteoglycan synthesis,108so the aggrecan and wa-
ter content of a decompressed nucleus would progres-
sively decrease, which is the opposite of what is required
to restore normal disc function.
Similarly, the high stress concentrations generated in
the anulus after endplate damage would also be expected
to inhibit matrix synthesis and increase production of
MMPs.109Therefore, in both regions of the disc, cells
would behave inappropriately because structural disrup-
tion has uncoupled their local mechanical environment
from the overall loading of the disc. Like a collapsed
house, a disrupted disc can no longer perform its func-
tion, even though its constituent parts remain. Cellular
attempts at repair become futile, not because the cells are
deficient, but because their local mechanical environ-
ment has become abnormal. In this way, structural dis-
ruption of the disc progresses by physical and biologic
methods, and the process represents degeneration rather
Defining disc degeneration in terms of structural fail-
ure allows all other features of degenerated discs to be
considered as predisposing factors for, or consequences
of, the disruption. Genetic inheritance and impaired me-
tabolite transport make the disc matrix physically weaker
and, so, more vulnerable to injury; so too can age-related
changes in collagen cross-linking, and loss of water and
Figure 8. “Stress profiles” from a cadaveric lumbar disc showing
the distribution of compressive stress across the disc’s sagittal
midline, before and after fracture of the vertebral endplate. End-
plate fracture reduces compressive stress in the anterior and
central regions of the adjacent disc, and generates a stress concen-
tration in the posterior anulus35(left).
2157What is Disc Degeneration?•Adams and Roughley
proteoglycan from the nucleus. Increased levels of cyto-
kines and MMPs probably reflect the initial features of
an attempted repair response to injury, as in other con-
nective tissues, and they could be triggered by the abnor-
mal matrix stresses which follow structural disruption
(Figure 8). However, because of impaired matrix synthe-
sis, subsequent repair is never achieved. Transport of
catabolic mediators within the disc would also be
boosted by the presence of gross fissures, thereby prop-
agating matrix damage. Finally, ingrowth of blood ves-
sels and nerves probably represent a late consequence of
altered mechanics and biochemistry in severely degener-
ated discs. Therefore, defining disc degeneration in terms
of structural failure leads to a simple conceptual frame-
work, which incorporates most known features of de-
generated discs. It also warns that therapeutic attempts
to manipulate disc cell physiology may prove futile un-
less the cells’ mechanical environment is also corrected.
This definition is also consistent with the 4 or 5-point
scales conventionally used to grade macroscopic “disc de-
generation.”40,110,111The first point on these scales refers
to end-stage degeneration, typified by a collapse of disc
height (Figure 6D). These scales are exercises in “pattern
recognition,” and although useful, they do not explain or
eration are compatible with the definition proposed here:
“mechanicaldamagewhich . . . resultsinapatternofmor-
phologic and histologic changes”112; and “sluggish adap-
tation to gravity loading followed by obstructed heal-
disc degeneration with associated structural changes.1
tions between “pathologic” and “age-related” changes in
discs, and included major structural changes such as radial
fissures and disc narrowing in the former category.113Re-
ferring to tendon degeneration, Riley et al102suggests “an
active, cell-mediated process that may result from a failure
to regulate specific MMP activities in response to repeated
injury or mechanical strain.” There is a growing consensus
that “degeneration” involves aberrant cell-mediated re-
sponses to progressively deteriorating circumstances in
their surrounding matrix.
Therefore, we propose the following definitions. The
response to progressive structural failure. A degenerate
disc is one with structural failure combined with accel-
erated or advanced signs of aging. (The second half of
this definition distinguishes a degenerate disc from one
that has just been injured, and the reference to “aging”
avoids the practical problem of identifying specific cell-
mediated responses to structural failure.) Early degener-
ative changes should refer to accelerated age-related
changes in a structurally intact disc. Degenerative disc
disease should be applied to a degenerated disc, which is
also painful. This last definition is consistent with the
widespread use of the word disease to denote something
that can cause distress or dis-ease. Manifestations of
structural failure such as radial fissures, disc prolapse,
endplate damage, internal or external collapse of the
anulus, and disc narrowing can themselves be defined in
pragmatic terms as is usual in the epidemiologic and
radiologic literature.65,113,114Cell-mediated responses
to structural failure can be regarded as the “final com-
mon pathway” of the disease process.
Interpretation: What Causes Disc Degeneration?
The aforementioned definitions simplify the issue of cau-
to degenerate by disrupting its structure and precipitat-
ing a cascade of nonreversible cell-mediated responses
leading to further disruption. As discussed previously,
and in detail elsewhere,4cadaveric experiments and
mathematical models show how various combinations
of compression, bending, and torsion can cause all the
major structural features of disc degeneration, including
endplate defects, radial fissures, radial bulging, disc pro-
lapse, and internal collapse of the anulus. Injury or wear-
and-tear “fatigue” loading can create damage. Animal
experiments confirm that structural disruption to disc
or endplate always leads to cell-mediated degenerative
Although we suggest that mechanical loading precipi-
tates degeneration, the most important cause of degenera-
tion could be the various processes that weaken a disc be-
fore disruption, or that impair its healing response. The
inadequate metabolite transport, and loading history ap-
pear to weaken some discs to such an extent that physical
disruption follows some minor incident. A common exam-
ple is that of disc herniation following a cough or sneeze. It
could be argued that such a weakened disc should be con-
sidered degenerated, even if it remains structurally sound.
However, a disc is unlikely to become painful until it be-
comes disrupted, so there is little to be gained by anticipat-
ing future events and applying the term “degeneration”
before this crucial nonreversible event actually occurs. As
suggested previously, accelerated biochemical or cellular
events in a structurally sound disc could be designated
“early degenerative changes” to distinguish them from
changes that are entirely typical of the disc’s age. The mul-
tifactorial nature of disc weakening suggests that, from a
medicolegal standpoint, all discs are “vulnerable” to a
greater or lesser extent, and the vulnerability can only be
gauged from the violence, or otherwise, required to disrupt
the disc and initiate degeneration.
The process of disc degeneration should be defined as an
aberrant, cell-mediated response to progressive struc-
tural failure. Definitions of a degenerated disc and early
degenerative changes should also refer to structural fail-
ure, whereas degenerative disc disease should apply to a
degenerated disc, which is also painful. The underlying
cause of disc degeneration is tissue weakening occur-
ring primarily from genetic inheritance, aging, nutri-
2158Spine•Volume 31•Number 18•2006
tional compromise, and loading history. The precipi-
tating cause is structural disruption occurring from
injury or fatigue failure.
● Intervertebral disc degeneration needs to be de-
fined for scientific and medicolegal reasons.
● We propose the following working definition to
stimulate further discussion: disc degeneration is
an aberrant cell-mediated response to progressive
● Disc structural failure is irreversible, always
progresses by physical and biologic mechanisms,
and is closely associated with mechanical dysfunc-
tion and pain.
● Genetic inheritance, age, inadequate metabolite
transport, and loading history can weaken discs to
such an extent that structural failure occurs during
the activities of daily living.
1. Battie MC, Videman T, Parent E. Lumbar disc degeneration: Epidemiology
and genetic influences. Spine 2004;29:2679–90.
Summary. Spine 2004;29:2677–8.
3. AO Spine research symposium. Spinal motion segment: From basic science
to clinical application. July 4–7, 2005; Davos, Switzerland.
4. Adams MA, Bogduk N, Burton K, et al. The Biomechanics of Back Pain.
Edinburgh, UK: Churchill Livingstone; 2002.
5. McDevitt CA. In: Ghosh P, ed. Biology of the Intervertebral Disc. Boca
Raton, FL: CRC Press; 1988:151–70.
6. Watanabe H, Yamada Y, Kimata K. Roles of aggrecan, a large chondroitin
7. Nerlich AG, Weiler C, Weissbach S, et al. Age-associated changes in the cell
density of the human lumbar intervertebral disc. Presented at: The 51st
Annual Meeting of the Orthopaedic Research Society; Feb 20–23, 2005;
8. Urban JP, Smith S, Fairbank JC. Nutrition of the intervertebral disc. Spine
9. Setton LA, Chen J. Cell mechanics and mechanobiology in the interverte-
bral disc. Spine 2004;29:2710–23.
10. Ferguson SJ, Ito K, Nolte LP. Fluid flow and convective transport of solutes
within the intervertebral disc. J Biomech 2004;37:213–21.
11. Roberts S, Menage J, Eisenstein SM. The cartilage end-plate and interver-
12. Horner HA, Urban JP. 2001 Volvo Award Winner in Basic Science Studies:
Effect of nutrient supply on the viability of cells from the nucleus pulposus
of the intervertebral disc. Spine 2001;26:2543–9.
13. Rajasekaran S, Naresh Babu J, Arun R, et al. ISSLS prize winner. A study of
diffusion in human lumbar discs. Spine 2004;29:2654–67.
14. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of met-
alloproteinases: Structure, function, and biochemistry. Circ Res 2003;92:
15. Mott JD, Werb Z. Regulation of matrix biology by matrix metalloprotein-
ases. Curr Opin Cell Biol 2004;16:558–64.
16. Duffy MJ, Lynn DJ, Lloyd AT, et al. The ADAMs family of proteins: From
basic studies to potential clinical applications. Thromb Haemost 2003;89:
17. Tang BL. ADAMTS: A novel family of extracellular matrix proteases. Int
J Biochem Cell Biol 2001;33:33–44.
18. Porter S, Clark IM, Kevorkian L, et al. The ADAMTS metalloproteinases.
Biochem J 2005;386:15–27.
19. Roberts S, Caterson B, Menage J, et al. Matrix metalloproteinases and
aggrecanase: Their role in disorders of the human intervertebral disc. Spine
20. Goupille P, Jayson MI, Valat JP, et al. Matrix metalloproteinases: The clue
to intervertebral disc degeneration? Spine 1998;23:1612–26.
21. Antoniou J, Steffen T, Nelson F, et al. The human lumbar intervertebral
disc: Evidence for changes in the biosynthesis and denaturation of the ex-
tracellular matrix with growth, maturation, ageing, and degeneration.
J Clin Invest 1996;98:996–1003.
22. Urban JP, Roberts S, Ralphs JR. The nucleus of the intervertebral disc from
development to degeneration. Am Zool 2000;40:53–61.
23. Adams MA, Dolan P. Could sudden increases in physical activity cause
degeneration of intervertebral discs? Lancet 1997;350:734–5.
24. Adams MA, Hutton WC. Prolapsed intervertebral disc. A hyperflexion
injury 1981 Volvo Award in Basic Science. Spine 1982;7:184–91.
25. Kang JD, Georgescu HI, McIntyre-Larkin L, et al. Herniated lumbar inter-
vertebral discs spontaneously produce matrix metalloproteinases, nitric ox-
ide, interleukin-6, and prostaglandin E2. Spine 1996;21:271–7.
26. Nerlich AG, Schleicher ED, Boos N. 1997 Volvo Award winner in basic
science studies. Immunohistologic markers for age-related changes of hu-
man lumbar intervertebral discs. Spine 1997;22:2781–95.
27. Weiler C, Nerlich AG, Zipperer J, et al. 2002 SSE Award Competition in
Basic Science: Expression of major matrix metalloproteinases is associated
with intervertebral disc degradation and resorption. Eur Spine J 2002;11:
28. Duance VC, Crean JK, Sims TJ, et al. Changes in collagen cross-linking in
degenerative disc disease and scoliosis. Spine 1998;23:2545–51.
29. Gruber HE, Hanley EN Jr. Ultrastructure of the human intervertebral disc
during aging and degeneration: Comparison of surgical and control speci-
mens. Spine 2002;27:798–805.
30. Melrose J, Ghosh P, Taylor TK, et al. A longitudinal study of the matrix
fibrosus. J Orthop Res 1992;10:665–76.
31. Kaigle AM, Holm SH, Hansson TH. 1997 Volvo Award winner in biome-
lesion model. Spine 1997;22:2796–806.
32. Roughley PJ. Biology of intervertebral disc aging and degeneration: In-
volvement of the extracellular matrix. Spine 2004;29:2691–9.
33. Verzijl N, DeGroot J, Thorpe SR, et al. Effect of collagen turnover on the
accumulation of advanced glycation end products. J Biol Chem 2000;275:
34. Bradford DS, Oegema TR Jr, Cooper KM, et al. Chymopapain, chemo-
nucleolysis, and nucleus pulposus regeneration. A biochemical and biome-
chanical study. Spine 1984;9:135–47.
35. Adams MA, Freeman BJ, Morrison HP, et al. Mechanical initiation of
intervertebral disc degeneration. Spine 2000;25:1625–36.
36. Buckwalter JA. Aging and degeneration of the human intervertebral disc.
37. Urban JP, Roberts S. Degeneration of the intervertebral disc. Arthritis Res
38. DeGroot J, Verzijl N, Wenting-Van Wijk MJ, et al. Accumulation of ad-
vanced glycation end products as a molecular mechanism for aging as a risk
factor in osteoarthritis. Arthritis Rheum 2004;50:1207–15.
39. Boos N, Weissbach S, Rohrbach H, et al. Classification of age-related
changes in lumbar intervertebral discs: 2002 Volvo Award in basic science.
40. Adams MA, Dolan P, Hutton WC. The stages of disc degeneration as
revealed by discograms. J Bone Joint Surg Br 1986;68:36–41.
41. Maeda S, Kokubun S. Changes with age in proteoglycan synthesis in cells
cultured in vitro from the inner and outer rabbit annulus fibrosus. Re-
sponses to interleukin-1 and interleukin-1 receptor antagonist protein.
42. Adams MA, McMillan DW, Green TP, et al. Sustained loading generates
stress concentrations in lumbar intervertebral discs. Spine 1996;21:434–8.
43. Ebara S, Iatridis JC, Setton LA, et al. Tensile properties of nondegenerate
human lumbar anulus fibrosus. Spine 1996;21:452–61.
44. Frobin W, Brinckmann P, Biggemann M, et al. Precision measurement of
disc height, vertebral height and sagittal plane displacement from lateral
45. Hirsch C, Schajowicz F. Studies on structural changes in the lumbar annu-
lus fibrosus. Acta Orthop Scand 1953;22:184–231.
46. Goel VK, Monroe BT, Gilbertson LG, et al. Interlaminar shear stresses and
laminae separation in a disc. Finite element analysis of the L3–L4 motion
segment subjected to axial compressive loads. Spine 1995;20:689–98.
47. Osti OL, Vernon-Roberts B, Moore R, et al. Annular tears and disc degen-
eration in the lumbar spine. A post-mortem study of 135 discs. J Bone Joint
Surg Br 1992;74:678–82.
48. Hilton RC, Ball J. Vertebral rim lesions in the dorsolumbar spine. Ann
Rheum Dis 1984;43:302–7.
2159What is Disc Degeneration?•Adams and Roughley
49. Jensen MC, Brant-Zawadzki MN, Obuchowski N, et al. Magnetic reso-
nance imaging of the lumbar spine in people without back pain. N Engl
J Med 1994;331:69–73.
50. Vernon-Roberts B, Fazzalari NL, Manthey BA. Pathogenesis of tears of the
51. Adams MA, Hutton WC. Gradual disc prolapse. Spine 1985;10:524–31.
52. Gordon SJ, Yang KH, Mayer PJ, et al. Mechanism of disc rupture. A pre-
liminary report. Spine 1991;16:450–6.
53. Gallagher S. Letter to the editor. Spine 2002;27:1378–9.
54. Moore RJ, Vernon-Roberts B, Fraser RD, et al. The origin and fate of
herniated lumbar intervertebral disc tissue. Spine 1996;21:2149–55.
of lumbar vertebrae. Ann Rheum Dis 1973;32:406–12.
56. Twomey L, Taylor J. Age changes in lumbar intervertebral discs. Acta
Orthop Scand 1985;56:496–9.
57. Holm S, Holm AK, Ekstrom L, et al. Experimental disc degeneration due to
endplate injury. J Spinal Disord Tech 2004;17:64–71.
58. Crock HV. Internal disc disruption. A challenge to disc prolapse fifty years
on. Spine 1986;11:650–3.
59. Gunzburg R, Parkinson R, Moore R, et al. A cadaveric study comparing
discography, magnetic resonance imaging, histology, and mechanical be-
havior of the human lumbar disc. Spine 1992;17:417–26.
60. Tanaka M, Nakahara S, Inoue H. A pathologic study of discs in the elderly.
Separation between the cartilaginous endplate and the vertebral body.
61. Adams MA, McNally DS, Dolan P. ‘Stress’ distributions inside interverte-
bral discs. The effects of age and degeneration. J Bone Joint Surg Br 1996;
healthy individuals and in patients with ongoing back problems. Spine
63. Brinckmann P, Grootenboer H. Change of disc height, radial disc bulge,
and intradiscal pressure from discectomy. An in vitro investigation on hu-
man lumbar discs. Spine 1991;16:641–6.
64. Pollintine P, Przybyla AS, Dolan P, et al. Neural arch load-bearing in old
and degenerated spines. J Biomech 2004;37:197–204.
65. Videman T, Battie MC, Gill K, et al. Magnetic resonance imaging findings
and their relationships in the thoracic and lumbar spine. Insights into the
etiopathogenesis of spinal degeneration. Spine 1995;20:928–35.
66. Bogduk N. The innervation of the intervertebral discs. In: Boyling JD,
Palastanga N, eds. Grieve’s Modern Manual Therapy–The Vertebral Col-
umn. Edinburgh, UK: Churchill Livingstone; 1994.
67. Freemont AJ, Peacock TE, Goupille P, et al. Nerve ingrowth into diseased
intervertebral disc in chronic back pain. Lancet 1997;350:178–81.
68. Palmgren T, Gronblad M, Virri J, et al. An immunohistochemical study of
nerve structures in the anulus fibrosus of human normal lumbar interver-
tebral discs. Spine 1999;24:2075–9.
69. Fagan A, Moore R, Vernon Roberts B, et al. ISSLS Prize Winner: The
innervation of the intervertebral disc: A quantitative analysis. Spine 2003;
sciatica: A report of pain response to tissue stimulation during operations
on the lumbar spine using local anesthesia. Orthop Clin North Am 1991;
71. McNally DS, Shackleford IM, Goodship AE, et al. In vivo stress measure-
ment can predict pain on discography. Spine 1996;21:2580–7.
72. Chen C, Cavanaugh JM, Song Z, et al. Effects of nucleus pulposus on nerve
root neural activity, mechanosensitivity, axonal morphology, and sodium
channel expression. Spine 2004;29:17–25.
73. Videman T, Battie MC, Gibbons LE, et al. Associations between back pain
history and lumbar MRI findings. Spine 2003;28:582–8.
spine disc degeneration: The Chingford Study. Arthritis Rheum 2003;48:
75. Moneta GB, Videman T, Kaivanto K, et al. Reported pain during lumbar
discography as a function of anular ruptures and disc degeneration. A
re-analysis of 833 discograms. Spine 1994;19:1968–74.
76. Videman T, Nurminen M. The occurrence of anular tears and their relation
to lifetime back pain history: A cadaveric study using barium sulfate dis-
cography. Spine 2004;29:2668–76.
77. Schwarzer AC, Aprill CN, Derby R, et al. The prevalence and clinical
features of internal disc disruption in patients with chronic low back pain.
78. Hamanishi C, Kawabata T, Yosii T, et al. Schmorl’s nodes on magnetic
resonance imaging. Their incidence and clinical relevance. Spine 1994;19:
79. Boos N, Rieder R, Schade V, et al. 1995 Volvo Award in clinical sciences.
The diagnostic accuracy of magnetic resonance imaging, work perception,
and psychosocial factors in identifying symptomatic disc herniations. Spine
80. Lotz JC. Animal models of intervertebral disc degeneration: Lessons
learned. Spine 2004;29:2742–50.
studies. Anulus tears and intervertebral disc degeneration. An experimental
study using an animal model. Spine 1990;15:762–7.
82. Moore RJ, Vernon-Roberts B, Osti OL, et al. Remodeling of vertebral bone
after outer anular injury in sheep. Spine 1996;21:936–40.
loading. J Biomech 2004;37:329–37.
84. Issever AS, Walsh A, Lu Y, et al. Micro-computed tomography evaluation
of trabecular bone structure on loaded mice tail vertebrae. Spine 2003;28:
85. MacLean JJ, Lee CR, Grad S, et al. Effects of immobilization and dynamic
compression on intervertebral disc cell gene expression in vivo. Spine 2003;
86. Hutton WC, Ganey TM, Elmer WA, et al. Does long-term compressive
loading on the intervertebral disc cause degeneration? Spine 2000;25:
87. Hutton WC, Murakami H, Li J, et al. The effect of blocking a nutritional
pathway to the intervertebral disc in the dog model. J Spinal Disord Tech
88. Lotz JC, Colliou OK, Chin JR, et al. Compression-induced degeneration of
the intervertebral disc: An in vivo mouse model and finite-element study.
89. Kerttula LI, Serlo WS, Tervonen OA, et al. Post-traumatic findings of the
spine after earlier vertebral fracture in young patients: Clinical and MRI
study. Spine 2000;25:1104–8.
90. Sambrook PN, MacGregor AJ, Spector TD. Genetic influences on cervical
and lumbar disc degeneration: A magnetic resonance imaging study in
twins. Arthritis Rheum 1999;42:366–72.
91. Paassilta P, Lohiniva J, Goring HH, et al. Identification of a novel common
genetic risk factor for lumbar disk disease. JAMA 2001;285:1843–9.
92. Kawaguchi Y, Osada R, Kanamori M, et al. Association between an aggre-
can gene polymorphism and lumbar disc degeneration. Spine 1999;24:
93. Videman T, Gibbons LE, Battie MC, et al. The relative roles of intragenic
and bone density. Spine 2001;26:E7-12.
94. Takahashi M, Haro H, Wakabayashi Y, et al. The association of degener-
ation of the intervertebral disc with 5a/6a polymorphism in the promoter of
the human matrix metalloproteinase-3 gene. J Bone Joint Surg Br 2001;83:
95. Seki S, Kawaguchi Y, Chiba K, et al. A functional SNP in CILP, encoding
cartilage intermediate layer protein, is associated with susceptibility to lum-
bar disc disease. Nat Genet 2005;37:607–12.
96. Videman T, Sarna S, Battie MC, et al. The long-term effects of physical
loading and exercise lifestyles on back-related symptoms, disability, and
spinal pathology among men. Spine 1995;20:699–709.
97. Battie MC, Videman T, Gill K, et al. 1991 Volvo Award in clinical sciences.
Smoking and lumbar intervertebral disc degeneration: An MRI study of
identical twins. Spine 1991;16:1015–21.
98. Kelsey JL, Githens PB, White AA III, et al. An epidemiologic study of lifting
and twisting on the job and risk for acute prolapsed lumbar intervertebral
disc. J Orthop Res 1984;2:61–6.
99. Oxford English Dictionary. Oxford University Press. Available at:
100. Le Maitre CL, Freemont AJ, Hoyland JA. Localization of degradative en-
zymes and their inhibitors in the degenerate human intervertebral disc.
J Pathol 2004;204:47–54.
101. Le Maitre CL, Freemont AJ, Hoyland JA. The role of interleukin-1 in the
pathogenesis of human intervertebral disc degeneration. Arthritis Res Ther
102. Riley GP, Curry V, DeGroot J, et al. Matrix metalloproteinase activities
and their relationship with collagen remodelling in tendon pathology. Ma-
trix Biol 2002;21:185–95.
103. Anderson DG, Li X, Tannoury T, et al. A fibronectin fragment stimulates
intervertebral disc degeneration in vivo. Spine 2003;28:2338–45.
104. Nissi MJ, Toyras J, Laasanen MS, et al. Proteoglycan and collagen sensitive
MRI evaluation of normal and degenerated articular cartilage. J Orthop
105. Melrose J, Roberts S, Smith S, et al. Increased nerve and blood vessel
ingrowth associated with proteoglycan depletion in an ovine anular lesion
model of experimental disc degeneration. Spine 2002;27:1278–85.
2160 Spine•Volume 31•Number 18•2006
106. Johnson WE, Caterson B, Eisenstein SM, et al. Human intervertebral disc
aggrecan inhibits nerve growth in vitro. Arthritis Rheum 2002;46:2658–64.
107. Johnson WE, Caterson B, Eisenstein SM, et al. Human intervertebral disc
108. Ishihara H, McNally DS, Urban JP, et al. Effects of hydrostatic pressure on
matrix synthesis in different regions of the intervertebral disk. J Appl
109. Handa T, Ishihara H, Ohshima H, et al. Effects of hydrostatic pressure on
matrix synthesis and matrix metalloproteinase production in the human
lumbar intervertebral disc. Spine 1997;22:1085–91.
110. Thompson JP, Pearce RH, Schechter MT, et al. Preliminary evaluation of a
scheme for grading the gross morphology of the human intervertebral disc.
111. Pfirrmann CW, Metzdorf A, Zanetti M, et al. Magnetic resonance classifi-
cation of lumbar intervertebral disc degeneration. Spine 2001;26:1873–8.
112. Freemont AJ, Watkins A, Le Maitre C, et al. Current understanding of
cellular and molecular events in intervertebral disc degeneration: Implica-
tions for therapy. J Pathol 2002;196:374–9.
113. Fardon DF. Nomenclature and classification of lumbar disc pathology.
114. Solovieva S, Lohiniva J, Leino-Arjas P, et al. COL9A3 gene polymorphism
and obesity in intervertebral disc degeneration of the lumbar spine: Evi-
dence of gene-environment interaction. Spine 2002;27:2691–6.
2161 What is Disc Degeneration?•Adams and Roughley