Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc and characteristics of intervertebral disc degeneration

Article (PDF Available)inThe Veterinary Journal 195(3) · November 2012with444 Reads
DOI: 10.1016/j.tvjl.2012.10.024 · Source: PubMed
Abstract
Intervertebral disc (IVD) degeneration is common in dogs and can give rise to a number of diseases, such as IVD herniation, cervical spondylomyelopathy, and degenerative lumbosacral stenosis. Although there have been many reports and reviews on the clinical aspects of canine IVD disease, few reports have discussed and reviewed the process of IVD degeneration. In this first part of a two-part review, the anatomy, physiology, histopathology, and biochemical and biomechanical characteristics of the healthy and degenerated IVD are described. In Part 2, the aspects of IVD degeneration in chondrodystrophic and non-chondrodystrophic dog breeds are discussed in depth.

Figures

Review
Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology
of the intervertebral disc and characteristics of intervertebral disc degeneration
Niklas Bergknut
a,b,
,1
, Lucas A. Smolders
a,1
, Guy C.M. Grinwis
c
, Ragnvi Hagman
b
, Anne-Sofie Lagerstedt
b
,
Herman A.W. Hazewinkel
a
, Marianna A. Tryfonidou
a
, Björn P. Meij
a
a
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3508 TD Utrecht, The Netherlands
b
Department of Clinical Sciences, Division of Small Animals, Faculty of Veterinary Medicine and Animal Sciences, Swedish University of Agricultural Sciences, Ulls väg 12, Box 7040,
750 07 Uppsala, Sweden
c
Department of Pathobiology, Pathology Division, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TD Utrecht, The Netherlands
article info
Article history:
Available online xxxx
Keywords:
Intervertebral disc
Degeneration
Dog
Chondrodystrophic
Non-chondrodystrophic
abstract
Intervertebral disc (IVD) degeneration is common in dogs and can give rise to a number of diseases, such
as IVD herniation, cervical spondylomyelopathy, and degenerative lumbosacral stenosis. Although there
have been many reports and reviews on the clinical aspects of canine IVD disease, few reports have dis-
cussed and reviewed the process of IVD degeneration. In this first part of a two-part review, the anatomy,
physiology, histopathology, and biochemical and biomechanical characteristics of the healthy and degen-
erated IVD are described. In Part 2, the aspects of IVD degeneration in chondrodystrophic and non-
chondrodystrophic dog breeds are discussed in depth.
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
The canine spine consists of 7 cervical, 13 thoracic, 7 lumbar, 3
(fused) sacral, and a variable number of coccygeal vertebrae
(Hansen, 1952; Dyce et al., 2010). The vertebral bodies of C2-S1
and all coccygeal vertebrae are interconnected by an intervertebral
disc (IVD) (Dyce et al., 2010). The IVD is composed of a central nu-
cleus pulposus (NP), an outer annulus fibrosus (AF), the transition
zone (TZ), and cartilaginous endplates (EPs) (Fig. 1).
Degeneration of the IVD is a common phenomenon in dogs and
can lead to disease (Brisson, 2010; da Costa et al., 2006; Meij and
Bergknut, 2010). IVD degeneration is known to predispose
dogs to Hansen type I cervical and thoracolumbar disc herniation
(Hansen, 1952) and Hansen type II disc herniation diseases, such
as degenerative lumbosacral stenosis (DLSS) (Meij and Bergknut,
2010) and cervical spondylomyelopathy (CSM) (da Costa et al.,
2006). However, IVD degeneration is also a common incidental
finding in dogs without clinical signs of disease (Hansen, 1952;
da Costa et al., 2006; De Decker et al., 2010).
The first case report of IVD degenerative disease in a dog was
published in 1881 and involved a Dachshund with sudden onset
of hind limb paralysis (Janson, 1881, cited by Hansen, 1952); the
mass that compressed the spinal cord was described as a
chondroma located only to the epidural space’. Shortly afterwards,
in 1896, a more comprehensive study was published on ‘enchond-
rosis intervertebralis’ (Dexler, 1896, cited by Hansen, 1952), a
reactive inflammation in the epidural space, but it would take an-
other 40 years before that disease was correctly described in the
veterinary literature as the herniation of NP material into the spinal
canal, causing compression of the spinal cord (Tillmanns, 1939).
Pioneering studies of IVD degeneration in dogs were performed
during the 1950s by the Swedish veterinarians Hansen and Olsson,
in particular the study that led to the thesis by Hans-Jörgen Hansen
in 1952 (Fig. 2)(Hansen, 1951, 1952, 1959; Olsson, 1951; Olsson
and Hansen, 1952). Since their studies, numerous publications
have described the clinical aspects of IVD degenerative diseases,
but few have revisited the fundamental aspects of IVD degenera-
tion (Braund et al., 1975, 1976; Ghosh et al., 1975, 1976a,b,
1977a,b; Cole et al., 1985, 1986; Gillett et al., 1988; Royal et al.,
2009; Johnson et al., 2010). The aim of this two-part review was
to summarize current literature on canine IVD degeneration. In this
first part, the anatomy, physiology, histopathology, and biochemi-
cal and biomechanical characteristics of the healthy and degener-
ated IVD are described. In Part 2, aspects of IVD degeneration in
chondrodystrophic and non-chondrodystrophic dog breeds are dis-
cussed (Smolders et al., 2012a).
1090-0233/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tvjl.2012.10.024
Corresponding author at: Department of Clinical Sciences of Companion
Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3508
TD Utrecht, The Netherlands. Tel.: +31 30 2531693.
E-mail address: N.Bergknut@uu.nl (N. Bergknut).
1
These authors contributed equally to the work.
The Veterinary Journal xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
The Veterinary Journal
journal homepage: www.elsevier.com/locate/tvjl
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
Embryology of the canine spine and intervertebral disc (IVD)
Three somatic germ layers are formed early in mammalian
embryogenesis: an outer ectodermal layer, a middle mesodermal
layer, and an inner endodermal layer (Vejlsted, 2010). A longitudi-
nal column of mesoderm, the notochord, establishes the cranial/
caudal and posterior/anterior axes of the developing embryo
(Fig. 3)(Vejlsted, 2010). Ectoderm directly posterior to the noto-
chord gives rise to the neural plate, which is composed of so-called
neuroectoderm. The neural tube and neural crest cells (positioned
dorsolateral to the neural tube) are formed from the neuroecto-
derm and give rise to the central nervous system and peripheral
nervous system, respectively (Vejlsted, 2010).
During the development of the neural tube, mesoderm adjacent
to the developing neural tube forms a thickened column of cells,
the paraxial mesoderm. The paraxial mesoderm ultimately devel-
ops into discrete blocks, the somites, which form the axial skeleton,
the associated musculature, and the overlying dermis. Each somite
is divided into: (1) a dermatome, which gives rise to dermis; (2) a
myotome, which gives rise to epaxial musculature; and (3) a scle-
rotome, which gives rise to vertebral structures (Vejlsted, 2010).
Sclerotomal cells form a continuous tube of mesenchymal cells,
the perichordal tube, which completely surrounds the notochord.
An alternating series of dense and less dense accumulations of cells
form along the perichordal tube, a process called resegmentation
(Sinowatz, 2010). While the bodies of the vertebrae develop from
the less dense accumulations, the dense accumulations form the
AF and TZ of the IVD, intervertebral ligaments, vertebral arches,
and vertebral processes, of which the latter two eventually fuse
with their corresponding vertebral body (Sinowatz, 2010). The for-
mation of the vertebral bodies results in segmentation of the noto-
chord, which persists as separate portions in each intervertebral
space. These separate portions of notochord expand, forming the
NP of the individual IVDs (Sinowatz, 2010; McCann et al., 2011).
The healthy canine intervertebral disc
Anatomy and physiology of the intervertebral disc
The healthy IVD is composed of four distinct components,
namely, the NP, AF, EP and TZ. The NP is a mucoid, translucent,
bean-shaped structure, mainly composed of water, located slightly
Fig. 1. Transverse (A) and sagittal (B) sections through a L5–L6 intervertebral disc
of a mature non-chondrodystrophic dog, showing the nucleus pulposus (NP),
transition zone (TZ), annulus fibrosus (AF), and endplates (arrowheads).
Fig. 2. (A) Title page of the thesis written by Hans-Jörgen Hansen in 1952, providing the first clear description of intervertebral disc degeneration and herniation in dogs, and
the distinction between chondrodystrophic and non-chondrodystrophic breeds with regard to this process (discussed in Smolders et al. (2012a)). (B) Reproduction from
Hansen’s thesis (1952). The original figure legend reads as follows: ‘Dachshund, 6 years old. Disc 21 (L2–L3). Protrusion of type I. the picture shows the large dimensions of the
protrusion and demonstrates clearly its origin from nucleus. The annulus fibrosus rupture is situated close to the right side of the dorsal longitudinal ligament. Nucleus is the
site of a calcified necrosis and has lost its normal shape’. (C) Reproduction from Hansen’s thesis (1952). The original figure legend reads as follows: ‘Dachshund, 4 years old.
Disc 22 (L3–L4) with a calcified centre and a dorsomedian rupture of the a.f. the protrusion is of type I with loose consistency and rough, uneven surface. An interlamellar
dissection of calcified material is seen to the left o nucleus, emanating from a ventral rupture of the inner layer of the a.f. this rupture, however, is not seen in this picture’ (a.f.,
annulus fibrosus).
2 N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
eccentrically in the IVD (Hukins, 1988; Johnson et al., 2010). The
NP is surrounded by the AF, a dense network of multiple, orga-
nized, concentric fibrous lamellae. The ventral part of the AF is
two to three times thicker than the dorsal part (Hansen, 1952).
Near the centre of the IVD, the AF becomes more cartilaginous
and less fibrous (Hansen, 1952; Hukins, 1988). This transition from
a fibrous to a more cartilaginous/mucoid structure, the TZ or the
innermost AF, forms the interconnection between the NP and AF
(Butler, 1988). The cranial and caudal borders of the IVD are
formed by the cartilaginous EPs (Hukins, 1988). The fibres of the
inner AF are strongly connected with the EPs, whereas the fibres
of the outer AF form connections with the bony vertebral body
epiphyses (Sharpey’s fibres) (Hansen, 1952; Inoue, 1981; Hukins,
1988).
The outer layers of the AF have a limited blood supply, but there
is no direct blood supply to the inner layers of the AF or to the NP.
However, terminal branches of the vertebral epiphyseal arteries
give rise to a densely woven vascular network adjacent to the car-
tilaginous EPs (Crock and Goldwasser, 1984). Innervation of the
IVD tissue itself is sparse: nerve endings have only been found in
the outer lamellae of the AF, and not in the inner AF, TZ, and NP
(Hansen, 1952; Forsythe and Ghoshal, 1984; Willenegger et al.,
2005). This is in contrast with the dorsal longitudinal ligament,
which is densely innervated (Hansen, 1952; Forsythe and Ghoshal,
1984).
The EPs play an essential role in supplying the IVD with nutri-
ents. Small molecules (such as oxygen and glucose) reach the cells
of the NP, TZ, and AF through diffusion and osmosis from the cap-
illary buds through the semipermeable EPs (Holm et al., 1981;
Holm et al., 1982; Urban et al., 2004). Additional nutrients and oxy-
gen are supplied via the outer, vascularized parts of the AF (Holm
et al., 1982; Maroudas, 1988). Larger molecules, such as albumin
and enzymes, are transported by bulk fluid flow (‘pumping mech-
anism’) created by the physiological loading of the IVD and
changes in posture (Holm et al., 1981, 1982; Maroudas, 1988;
Urban et al., 2004).
Histology of the healthy intervertebral disc
In the healthy IVD, the main cell of the NP is the notochordal
cell (Fig. 4C) (Hansen, 1952; Braund et al., 1975; Butler, 1988;
Cappello et al., 2006). These large cells are characterized by cyto-
plasmic vesicles, the content and function of which are still de-
bated (Hansen, 1952; Hunter et al., 2003, 2004), but there are
indications that these vesicles are unique organelles, which have
an osmoregulatory function, and that they are involved in the
swelling and stretching of the embryonic notochord and in the reg-
ulation of osmotic stresses in the NP (Hunter et al., 2007). The
notochordal cell has relatively few mitochondria and is therefore
thought to rely mainly on anaerobic metabolism (Hunter et al.,
2003). Notochordal cells are found in clusters (Hunter et al.,
2003, 2004) and produce an amorphous basophilic matrix rich in
proteoglycans and collagen type II (Hansen, 1952; Butler, 1988;
Hunter et al., 2003; Cappello et al., 2006).
The TZ contains chondrocyte-like cells embedded in a loose, aci-
dophilic fibrous matrix network (Hansen, 1952; Braund et al.,
1975; Ghosh et al., 1975) and is distinct from the matrix surround-
ing the notochordal cells (Butler, 1988). Microscopically, the lamel-
lae of the AF can be seen as separate fibrocartilaginous layers
composed of eosinophilic fibrous bundles arranged in parallel
(Figs. 4
B and 5)(Hansen, 1952; Braund et al., 1975; Butler,
1988). The cell population changes from fibrocyte-like cells in
the outer layers of the AF to a mixed population of fibrocytes and
chondrocyte-like cells in the inner layers (Hansen, 1952; Braund
Fig. 3. (A) Schematic image of a transverse cross-section through the canine embryo, with the notochord (1), neural tube (2), neural crest cells (3), sclerotome (4), myotome
(5), and dermatome (6). (B) Schematic image of a transverse cross-section through the lumbar spine of a mature dog, with the nucleus pulposus (1), spinal cord (2), spinal
nerves (3), annulus fibrosus (4a) and transition zone, dorsal vertebral lamina (4b), transverse spinal process (4c), dorsal longitudinal ligament (4d), ventral longitudinal
ligament (4e), epaxial musculature (5), and skin (6). (C) Schematic image of a dorsal cross-section through the canine embryo, with the notochord (1), neural crest cells (3),
sclerotome (4), and myotome (5). (D) Schematic image of a dorsal cross-section through the lumbar spine of a mature dog, with the mature nucleus pulposus (1), spinal
nerves (3), annulus fibrosus (4a) and vertebral body (4b), and epaxial musculature (5). The colours of the structures of the mature animal correspond with the colours of their
embryological origin.
N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
3
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
et al., 1975; Butler, 1988; Bergknut et al., 2012a). The canine EP
(Fig. 4D) consists of cranio-caudally oriented layers of matrix and
chondrocyte-like cells (Inoue, 1981), on average 5 (3–8) cell layers
thick and comprises 6% (3–11%) of the total width (intervertebral
distance) of the canine IVD (Bergknut et al., 2012b).
Biochemical structure of the healthy intervertebral disc
The healthy NP is composed of a complex network of negatively
charged proteoglycans interwoven in a mesh of collagen fibres
(mainly collagen type II) (Ghosh et al., 1976a; Cole et al., 1985).
The proteoglycan molecules consist of a protein backbone with
negatively charged glycosaminoglycan (GAG) side chains. The most
common side chains are chondroitin sulfate and keratin sulfate,
which are covalently bound to the central core protein (Ghosh
et al., 1976a, 1977a,b; Cole et al., 1985, 1986). These negatively
charged GAGs repel each other, giving the proteoglycans the
appearance of a bottle-brush. The most common proteoglycan in
the healthy IVD is aggrecan (Cole et al., 1986). The proteoglycans
are in turn aggregated with hyaluronic acid, and these negatively
charged large complexes create a strong osmotic gradient, attract-
ing water into the NP. As a result, over 80% of the healthy NP is
composed of water (Holm and Nachemson, 1983), creating a high
intradiscal pressure (Ghosh et al., 1977a,b; Cole et al., 1985).
Fig. 4. (A) Mid-sagittal histological section (H&E) of a healthy, immature canine intervertebral disc, still with active growth plates in the vertebral bodies (
). (B) Annulus
fibrosus (AF), showing the lamellar layers with fibrocyte-like cells (arrowhead) and chondrocyte-like cells (arrow). (C) Nucleus pulposus (NP), showing clustered notochordal
cells. (D) Cartilaginous endplate (EP), showing chondrocyte-like cells in a hyaline-type matrix. The border between endplate (left) and subchondral bone (SCB) (right) is
indicated with arrowheads.
Fig. 5. An electron microscopy image of the annulus fibrosus from a healthy canine, lumbar intervertebral disc. The overview to the left shows the well-organized lamellar
layers. To the right, a higher resolution image showing the individual collagen bundles. Photos courtesy of Andrea Friedmann.
4 N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
The lamellae of the AF are composed of collagen fibrils aggre-
gated with elastic fibres and coated by proteoglycans (Johnson
et al., 1984; Cole et al., 1985, 1986). The outer part of the AF con-
tains mostly collagen type I, whereas the inner part (TZ) contains
predominantly collagen type II. The AF consists of 60% water (Holm
and Nachemson, 1983).
The biochemical composition of the healthy EP is very similar to
that of articular cartilage (Roberts et al., 1989). The EP has a highly
hydrated matrix (50–80%) composed of proteoglycans intercon-
nected with hyaluronic acid and link proteins, and collagen
(mainly type II) (Roberts et al., 1989; Antoniou et al., 1996). The
biochemistry of the EP is critical for maintaining the integrity of
the IVD, since the proteoglycans in the matrix regulate the trans-
port of solutes into and from the IVD (Roberts et al., 1997).
The process of remodelling and breakdown of the extracellular
matrix in the IVD is regulated by enzymes such as matrix metallo-
proteinases (MMPs) and ADAMTS (a disintegrin and metallopro-
teinase with thrombospondin motifs), produced by the cells of
the IVD. While much is known about the activity of these regula-
tory enzymes in IVD remodelling in humans (Roughley, 2004), less
is known about their activity in dogs (Melrose et al., 1997).
Biomechanical function of the healthy intervertebral disc
The biomechanical function of the IVD is to transmit compres-
sive forces between vertebral bodies and to provide mobility as
well as stability to the spinal segment (White and Panjabi, 1978;
Adams and Hutton, 1988). Like in humans, the horizontally-
positioned spine in dogs is loaded along its longitudinal axis, which
is the result of contraction of the trunk muscles and the tension on
structures such as the ligaments (Zimmerman et al., 1992; Smit,
2002). Since relatively few biomechanical studies investigating
the canine IVD have been performed, we will also discuss studies
in humans.
During motion, the canine IVD can be subjected to several mo-
tions/loading conditions, namely axial compression, shear, tension,
bending, and torsion (White and Panjabi, 1978; Smit, 2002). The
NP, AF, TZ, and EPs work as a functional unit to resist these loads,
with each component having a different specialized function
(Hukins, 1988; Roughley, 2004; Setton and Chen, 2006). The NP
is a highly hydrated structure that exerts swelling pressure inside
the IVD. The EPs and AF function to contain the NP during loading.
During axial compression, the majority of the compressive load is
absorbed by the NP and the inner TZ. The surrounding AF protects
the NP against shearing induced by the applied load and its own
internal swelling pressure, thereby maintaining the disc circumfer-
ence in spite of a decrease in disc height. The alternating arrange-
ment of the annular lamellae, combined with the oblique
orientation of the lamellar fibres, enables the AF to cope with ten-
sile forces generated during loading (Adams and Hutton, 1988).
The IVD is rarely subjected to pure tensile loads, as the trunk
muscles constantly act to keep the IVD compressed. The mecha-
nism by which the IVD permits bending is essentially the same
for flexion, lateral flexion, and extension. During flexion, the hydro-
static pressure in the NP increases, and the obliquely running fibres
of the AF change their orientation. For example, in the transition
from neutral position to dorsoflexion, the compressive stress with-
in the NP increases on the dorsal side of the disc, the fibres of the
ventral AF extend, whereas those in the dorsal AF become com-
pressed, resulting in bulging of the dorsal AF. The capacity of the
IVD to resist bending is directly related to the volume of the NP:
if the nuclear volume is increased (by saline injection), the resis-
tance to bending increases (Adams and Hutton, 1988). In compar-
ison to bending motion, IVDs are stiffer in axial rotation/torsion
(Adams and Hukins, 1988).
Vertebral motion has been shown to cause an outflow of fluid
from the IVD, especially from the NP (Adams et al., 1996). Any out-
flow of fluid is reversed when the spine is unloaded. The diurnal
cycle of load-induced fluid expression and regain seems to have
important consequences for transport of large solutes and nutri-
ents, because factors affecting diffusion, such as disc height (diffu-
sion distance), are sensitive to hydration (Urban et al., 2004). This
is further illustrated by the finding that spinal motion over a longer
period of time increases the aerobic metabolism of IVD cells, there-
by decreasing the production of lactate (Holm and Nachemson,
1983). However, the effects of the diurnal cycle on the nutrition
of the canine IVD are still largely unknown.
The degenerating canine intervertebral disc
The characteristics of degeneration of the IVD discussed below
are applicable for chondrodystrophic (CD) and non-chondrody-
strophic (NCD) dog breeds. Specific differences regarding the char-
acteristics of IVD degeneration between CD and NCD dog breeds
are discussed in Part 2 of this review (Smolders et al., 2012a).
Intervertebral disc degeneration
Degeneration of the IVD is a complex, multifactorial process
that is characterized by changes in the composition of the cells
and extracellular matrix of the NP, TZ, AF, and EPs. The pathophys-
iology of IVD degeneration in dogs has been largely unexplored.
However, IVD degeneration in dogs is very similar to human IVD
degeneration (Bergknut et al., 2012b), and therefore the funda-
mental, pathophysiological processes involved in human IVD
degeneration will be briefly discussed.
IVD degeneration is described as an aberrant, cell-mediated re-
sponse to progressive structural failure of the IVD and is associated
with genetic predisposition, chronic physicomechanical overload
and trauma, inadequate metabolite and nutrient transport to and
from the cells with the IVD matrix, cell senescence and death, al-
tered levels of enzyme activity, changes in matrix macromolecules,
and changes in water content (Fig. 6)(Buckwalter, 1995; Adams
and Roughley, 2006). In the process of IVD degeneration, the
GAG content decreases with a concurrent increase in collagen con-
tent. As a result, the matrix of the IVD becomes more rigid and
loses its hydrostatic properties to function as a hydraulic cushion,
rendering the IVD matrix suboptimal to fulfil its biomechanical
function. Structural failure of the matrix results in a changed bio-
mechanical environment of the IVD cells within the matrix. In
addition, because of the changes of the IVD matrix, diffusion of
nutrients and the bulk fluid flow in and out of the disc become im-
paired, further deteriorating the health of the IVD cells and synthe-
sis of healthy matrix.
The avascular and low cellular nature of the IVD and the inferior
biomechanical environment eventually impair the ability of IVD
cells to adequately repair the matrix. The weakened IVD is vulner-
able to damage by levels of stress that are considered physiological
for the healthy IVD. Consequently, a vicious cycle of continued
damage and inadequate repair and regeneration is triggered,
resulting in degeneration rather than healing (Fig. 6). Structural
failure of the IVD manifests itself in characteristic macroscopic
changes. As a result of dehydration of the IVD (especially the
NP), the disc height (distance between two EPs) may decrease,
and due to the decreased functionality of the NP, the AF, and EPs
are loaded non-physiologically, eventually resulting in annular
tears and EP fractures, respectively (further discussed below).
Structural failure of the IVD as a whole may also result in bulging
or herniation of the IVD.
N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
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Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
The changes seen in early IVD degeneration closely resemble
those of physiological ageing of the disc. Although the definition
proposed by Adams and Roughley (2006) may partially distinguish
truly degenerative changes from age-related ones, it cannot be ap-
plied to the onset and early stages of IVD degeneration. Therefore,
we use the term ‘IVD degeneration’ to describe deterioration of the
quality of the IVD matrix as a result of pathological and age-related
changes and the associated structural changes of the disc, as de-
scribed below.
Macroscopic aspects of intervertebral disc degeneration
Thompson et al. (1990) described what is now accepted as the
gold standard for reproducible and objective grading of the macro-
scopic changes associated with IVD degeneration in humans, and
this grading scheme has been validated for use in dogs (Bergknut
et al., 2011). According to this scheme (Fig. 7; Table 1), the gradual
process of IVD degeneration can be divided into five stages, ranging
from a completely healthy IVD (grade I) to a severely degenerated
IVD (grade V). This grading scheme does not include herniation and
prolapse of the IVD, which are considered consequences of the
degenerative process (Hansen, 1952).
Degeneration commonly starts in the mucoid NP, which changes
colour from shining translucent grey to dull, non-translucent
white–grey or yellowish green–brown. These changes are accompa-
nied by cleft formation and ultimately collapse of the NP. As the NP
degenerates, the lamellar structure of the AF buckles inwards and be-
comes disorganized. The TZ widens and becomes irregular, making it
difficult to distinguish the AF from the NP (Hansen, 1952; Braund
et al., 1975; Ghosh et al., 1975; Cappello et al., 2006). The cartilagi-
nous EP thickens, becomes irregular and may fracture. New bone
may be formed at the peripheral margins of the vertebral bodies,
resulting in osteophytes and ventral spondylosis (Thompson et al.,
1990). Continued degeneration will lead to highly irregular and
sometimes breached EPs and subchondral bone. As degeneration
proceeds, the IVD space becomes smaller or may disappear com-
pletely in extreme cases, with bulging of the degenerated AF or even
rupturing of the AF and herniation of the NP.
Histopathology of intervertebral disc degeneration
The histopathological changes that occur during IVD degenera-
tion in dogs were first described by Hansen (1952), but few studies
of these changes have been published since (Braund et al., 1975;
Ghosh et al., 1975; Hunter et al., 2004; Royal et al., 2009; Johnson
Fig. 6. Generalized, schematic representation of the pathophysiology of intervertebral disc degeneration, illustrating the factors and the chain of events involved in the
degenerative cascade partly based on human literature. Intervertebral disc degeneration involves a vicious circle of repeated structural/functional failure and inadequate
repair of the intervertebral disc matrix. Several factors (green symbols) may initiate or affect/accelerate the degenerative cycle, and structural/functional failure may result in
various structural changes (red arrow) of the intervertebral disc and adjacent vertebral bodies.
6 N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
et al., 2010; Bergknut et al., 2012a,b). A new scheme for grading
histopathological changes in the canine IVD has recently been pro-
posed (Bergknut et al., 2012a) which not only evaluates the cellular
and structural changes in the AF, NP, and EPs (using hematoxylin
and eosin staining), but also uses specific stains (Alcian blue to
stain proteoglycans, and picrosirius red to stain collagens) to assess
changes in the extracellular matrix components (Fig. 8). The grad-
ing system also considers changes in tissues or structures adjacent
to the IVD, such as new bone formation and sclerotic changes in
subchondral bone.
The early stage of degeneration is characterized by cellular
changes within the NP. The large notochordal cell clusters are lost,
resulting in smaller notochordal cell clusters or single notochordal
cells (Fig. 9C). Concurrently, single or clusters of chondrocyte-like
cells, surrounded by extracellular matrix, appear in the NP, divid-
ing it into lobules, resulting in the gradual expansion of the TZ into
the NP (Fig. 9D) (Hansen, 1952; Bergknut et al., 2012a). In essence,
notochordal cells are replaced by chondrocyte-like cells and their
associated extracellular matrix, which resembles hyaline cartilage
and consists largely of disorganized collagen fibres. This process is
referred to as chondrification (Hansen, 1952; Braund et al., 1975;
Ghosh et al., 1975; Hunter et al., 2004; Cappello et al., 2006). While
chondrocyte-like cells may migrate from the TZ into the NP, recent
evidence suggests that it is more likely that they are of a differen-
tiated notochordal cell lineage (Choi et al., 2008; Risbud et al.,
2010; McCann et al., 2011). Degeneration of the extracellular ma-
trix of the NP can be observed as clefts and cracks, which are a re-
sult of the altered biochemical properties of the matrix.
Histologically, degeneration of the AF is characterized by the
disorganization of the lamellar fibres and the ingrowth of chondro-
cyte-like cells from the TZ (Fig. 9B) (Hansen, 1952; Bergknut et al.,
2012a). Cross-links between the annular fibres, which prevent
lamellar movement in the AF, are more numerous in degenerated
IVDs (Puustjarvi et al., 1993). The inability of normal AF movement
combined with NP degeneration and loss of IVD height may result
in rupture or bulging of the AF, resulting in IVD herniation (Hansen,
1952; Smolders et al., 2012a,b,c).
The EPs become thicker in the early stages of degeneration, and
in later stages become increasingly irregular and may breach at
several places (Fig. 9E). The breaches usually occur in the central
parts of the EPs and can give rise to a ‘Schmorls node’, which is her-
niation of the NP into the vertebral body (Schmorl, 1926).
Fig. 7. Mid-sagittal images depicting different stages (I to V) of canine intervertebral disc (IVD) degeneration according to validated macroscopic (top) and histopathological
(bottom) grading schemes, showing a healthy IVD at the far left and increasing severity of IVD degeneration going from left to right. Reprinted with permission from Spine
(Bergknut et al., 2012b).
Table 1
Description of the five categories of the macroscopic grading scheme for gross pathological changes of intervertebral discs according to Thompson (Thompson et al., 1990;
Bergknut et al., 2011).
Grade Nucleus pulposus Annulus fibrosus End-plates Vertebral bodies
I Bulging gel Discrete fibrous lamellae Hyaline, uniform thickness Rounded margins
II White fibrous tissue
peripherally
Mucinous material between lamellas Irregular thickness Pointed margins
III Consolidated fibrous
tissue
Extensive mucinous infiltration; loss of
annular-nuclear demarcation
Focal defects in cartilage Early chondrophytes or
osteophytes at margins
IV Horizontal (vertical) clefts
parallel to end-plate
Focal disruptions Fibrocartilage extending from subchondral bone;
irregularity and focal sclerosis in subchondral bone
Osteophytes <2 mm
V Clefts extend through
nucleus and annulus
Diffuse sclerosis Osteophytes >2 mm
Fig. 8. Mid-sagittal histological sections of a healthy and a moderately degenerated
canine intervertebral disc (IVD) stained with picrosirius red and Alcian blue. Alcian
blue stains proteoglycans light blue and picrosirius red stains principally collagen
type I red. In the healthy IVD (A), a clear distinction can be made between the
nucleus pulposus (NP) containing chiefly proteoglycans, and the annulus fibrosus
(AF) staining dark blue/purple, which indicates a mixture of proteoglycans and
collagen type I. In the degenerated IVD (B), no clear distinction between the NP and
AF can be made, with increasing collagen staining seen throughout the IVD. A cleft
transecting the NP can also be seen.
N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
7
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
Biochemical changes involved in intervertebral disc degeneration
IVD degeneration is associated with a decrease in proteoglycan
contents and in the degradation of GAG molecules of the NP, with
the long chondroitin sulfate side chains being replaced by shorter
keratin sulfate side chains (Ghosh et al., 1976a, 1977a,b; Cole
et al., 1985, 1986). The relative content of collagen also increases,
first in the NP and subsequently in the AF (Fig. 8)(Ghosh et al.,
1976a, 1977a,b). Little is known about the biochemical changes in-
volved in degeneration of the canine EPs. Degeneration of the hu-
man EP is accompanied by a decrease in the water, collagen type II,
and proteoglycan content (Antoniou et al., 1996) and ultimately in
mineralization (Oda et al., 1988), leading to obstruction of capillary
buds and obstruction of the physiological transport of solutes to
and from the IVD (Oda et al., 1988; Roberts et al., 1997).
MMPs are involved in remodelling and degeneration of the hu-
man disc and MMP-1 and -2 are responsible for the breakdown of
collagen types I and II, respectively. A correlation has been found
between an increase in MMP-2 and the severity of IVD degenera-
tion in dogs (Bergknut et al., 2012b). ADAMTS-4 causes the break-
down of aggrecan in human IVD degeneration (Mosyak et al.,
2008). The most important MMP inhibitors in the IVD are protease
inhibitors, called tissue inhibitors of metalloproteinase (TIMPs).
Inflammatory mediators that accelerate the degenerative process,
such as tumour necrosis factor (TNF)-
a
, interleukin (IL)-1b and
IL-6, have been identified in degenerated IVDs (Podichetty, 2007).
Biomechanical effects of intervertebral disc degeneration
The inability of the IVD to fulfil its physiological function inter-
feres with the normal action of the vertebral column, thereby influ-
encing other components of the functional spinal unit, such as
ligaments, facet joints, and vertebral bodies (Adams and Roughley,
2006). Therefore, deficits in the biomechanical quality and integrity
of the IVD caused by degeneration can lead to structural failure of
the functional spinal unit and ultimately to spinal cord compression.
The reduced proteoglycan content of the NP leads to dehydra-
tion and to a consequent loss of NP size and intradiscal pressure.
Consequently, the AF takes over the compressive load-bearing
function that is usually performed by the hydrated NP (McNally
and Adams, 1992; Adams et al., 1996a). As a result, the AF increases
in size (McNally and Adams, 1992; Johnson et al., 2010) and be-
comes stiffer and weaker, leading to structural failure, which pre-
vents the AF from resisting tensile forces. The degenerative
changes ultimately cause the IVD to bulge outwards when it is sub-
jected to physiological loading (Adams and Roughley, 2006). In addi-
tion, structural failure of the AF can result in annular defects or tears
(Adams and Roughley, 2006), through which degenerated NP mate-
rial can extrude (Hansen, 1952; Adams and Roughley, 2006). Since
the dorsal AF is 2–3 times thinner than the ventral AF, structural
failure and IVD herniation usually occur on the dorsal side.
Removal of the NP through an annular window in canine cadav-
eric spines, a procedure which resembles IVD herniation, causes
Fig. 9. (A) Mid-sagittal histological section (H&E) of a degenerated canine intervertebral disc. (B) Annulus fibrosus (AF), showing disorganization of the lamellar structure and
an increase in chondrocyte-like cells. (C) Nucleus pulposus (NP), showing dead (arrow) and dying (arrowhead) notochordal cells. (D) Nucleus pulposus, showing small groups
of chondrocyte-like cells (cell nests). (E) Cartilaginous endplate (EP), showing endplate irregularities and damage. The irregular border between the endplate and the
subchondral bone is marked with arrowheads.
8 N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
spinal instability, indicating that AF and NP integrity are essential
to the functionality of the spine (Schulz et al., 1996; Macy et al.,
1999; Hill et al., 2000; Smith et al., 2004; Smolders et al.,
2012a,b,c). Conversely, annular damage (fissures) may occur inde-
pendently of NP degeneration and is likely to result in increased
stress on the NP (Adams and Roughley, 2006). In addition to struc-
tural failure of the NP and AF with subsequent disc displacement,
degeneration of the NP and AF results in an uneven distribution
of load on the EP, making it more susceptible to damage. Degener-
ation of the IVD can therefore result in cracks in the EP with extru-
sion of the degenerated NP (Grant et al., 2002).
As a component of the functional spinal unit, degeneration of
the IVD affects not only the disc, but also other spinal components,
such as ligaments, facet joints, and vertebral bodies (Adams and
Roughley, 2006). Decreased IVD function alters and increases facet
joint loading (Kahmann et al., 1990), which can lead to secondary
osteoarthritic changes. The altered loading pattern can also affect
the adjacent vertebrae, leading to remodelling, sclerosis, and spon-
dylosis of the vertebral bodies (Keller et al., 1989).
With increasing degeneration (Thompson grades I to IV), the
stabilizing function of the IVD in relation to rotational biomechan-
ics (i.e., flexion/extension, lateral bending, axial rotation) is lost,
accompanied by an increase in the mobility of the affected spinal
segment. However, in the final stages (Thompson grade V) of IVD
degeneration, laxity decreases and the spine ‘restabilizes’ as a re-
sult of the formation of osteophytes/spondylosis and collapse of
the IVD space (Fujiwara et al., 2000; Smolders et al., 2012c).
Conclusions
The physiological function of the IVD, an essential structure of
the spine, is largely dependent on the quality of its extracellular
matrix and therefore of the ability of its constituent cells to synthe-
size, remodel, and maintain a biochemically healthy matrix.
Degeneration of the IVD involves significant cellular changes, with
a shift from the native notochordal cell population to a ‘subopti-
mal’ chondrocyte-like cell population. At the same time, the qual-
ity of the matrix deteriorates as a result of the changes in cellular
composition and of the aberrant homeostasis of the matrix and
matrix-regulating enzymes. This cascade of events ultimately leads
to structural failure of the AF, NP and EP. Since the individual com-
ponents of the IVD function synergistically, deterioration of one
component leads to degeneration of the other, resulting in a degen-
erative cascade that can lead to bulging or herniation of the IVD.
Conflict of interest statement
None of the authors of this paper has a financial or personal
relationship with other people or organisations that could inappro-
priately influence or bias the content of the paper.
Acknowledgments
The authors would like to thank the Multimedia Department of
the Faculty of Veterinary Medicine, Utrecht University for their
technical assistance.
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10 N. Bergknut et al. / The Veterinary Journal xxx (2012) xxx–xxx
Please cite this article in press as: Bergknut, N., et al. Intervertebral disc degeneration in the dog. Part 1: Anatomy and physiology of the intervertebral disc
and characteristics of intervertebral disc degeneration. The Veterinary Journal (2012), http://dx.doi.org/10.1016/j.tvjl.2012.10.024
    • "Canine intervertebral disc (IVD) disease is a frequent result of IVD degeneration [1, 2]. Diagnostic imaging is a useful tool to detect degenerative changes in IVDs [3]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Canine intervertebral disc degeneration can lead to intervertebral disc disease. Mild degenerative changes in the structure of the canine intervertebral disc can be identified in magnetic resonance images, whereas these changes are not visible in computed tomographic images. Therefore, one aim of this study was to detect whether colour-coded computed tomography enhances the visibility of mild degenerative changes in the canine disc structure compared to non-contrast computed tomography. Furthermore, the study aimed to detect if intervertebral disc degeneration could be classified with a higher reliability in colour-coded images than in non-contrast images. Results Computed tomographic image studies of 144 canine intervertebral discs were coloured using three different lookup tables. Canine intervertebral disc degeneration was evaluated by three observers using a 5-grade classification system and compared to the evaluation of non-contrast CT and MRI images. A moderate to almost perfect intraobserver and a moderate to substantial interobserver agreement were found depending on the used colour code. On comparing non-contrast and colour-coded CT significant differences were found by one observer only. Significant differences in evaluation were found in grading intervertebral disc degeneration in MRI and colour-coded CT. Conclusions Intervertebral disc degeneration could not be classified with a higher reliability on colour-coded images compared to non-contrast images. Furthermore, colour-coded CT did not enhance the visibility of mild degenerative changes in disc structure compared to non-contrast CT. However, the better intraobserver agreement and the subjective impression of the observers highlighted that the usage of colour encoded CT data sets with a wide range of tonal values of few primary and secondary colours may facilitate evaluation.
    Full-text · Article · Nov 2015
    • "In our present evaluation, intervertebral disk degeneration played a significant role in the disease process. Although canine disk degeneration can occur in any breed or mixed-breed, two breed groupings exist (Bergknut et al., 2013). In chondrodystrophic (CD) breeds, the intervertebral disk degenerates usually between 3 and 7 years of age and typically targets the cervical or thoracolumbar spine (Hansen, 1952; Olby et al., 2004; Brisson, 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: A mostly complete canine skeleton was excavated during rescue archaeological explorations in Domaslaw (Lower Silesia, Poland). The archaeozoological analysis revealed loss of several left maxillary incisors. Discospondylitis was observed in two adjacent lumbar vertebrae. Potential causes of the vertebral pathology are discussed. The cause of death is unknown, but sepsis should be considered. No other pathological changes or evidence of human manipulation to the skeleton were identified. (C) 2015 Published by Elsevier Inc.
    Full-text · Article · Sep 2015
    • "NCs are characterized by their morphology: they are large and have cytoplasmic vesicles, the content and function of which are still debated [8]. NCs are usually found in clusters and secrete matrix rich in proteoglycan and collagen type II [2]. They have considerable regenerative potential and restorative capacity for other cells (CLCs and MSCs), which makes them an interesting focus for regenerative strategies. "
    [Show abstract] [Hide abstract] ABSTRACT: Pain due to spontaneous intervertebral disc (IVD) disease is common in dogs. In chondrodystrophic (CD) dogs, IVD disease typically develops in the cervical or thoracolumbar spine at about 3-7 years of age, whereas in non-chondrodystrophic (NCD) dogs, it usually develops in the caudal cervical or lumbosacral spine at about 6-8 years of age. IVD degeneration is characterized by changes in the biochemical composition and mechanical integrity of the IVD. In the degenerated IVD, the content of glycosaminoglycan (GAG, a proteoglycan side chain) decreases and that of denatured collagen increases. Dehydration leads to tearing of the annulus fibrosus (AF) and/or disc herniation, which is clinically characterized by pain and/or neurological signs. Current treatments (physiotherapy, anti-inflammatory/analgesic medication, surgery) for IVD disease may resolve neurological deficits and reduce pain (although in many cases insufficient), but do not lead to repair of the degenerated disc. For this reason, there is interest in new regenerative therapies that can repair the degenerated disc matrix, resulting in restoration of the biomechanical function of the IVD. CD dogs are considered a suitable animal model for human IVD degeneration because of their spontaneous IVD degeneration, and therefore studies investigating cell-, growth factor-, and/or gene therapy-based regenerative therapies with this model provide information relevant to both human and canine patients. The aim of this article is to review potential regenerative treatment strategies for canine IVD degeneration, with specific emphasis on cell-based strategies.
    Full-text · Article · Jan 2014
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