The Veterinary Journal 195 (2013) 292299

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The Veterinary Journal

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Review

Intervertebral disc degeneration in the dog. Part 2: Chondrodystrophic and non-chondrodystrophic breeds
Lucas A. Smolders a,,1, Niklas Bergknut a,b,1, Guy C.M. Grinwis c, Ragnvi Hagman b, Anne-Soe Lagerstedt b, Herman A.W. Hazewinkel a, Marianna A. Tryfonidou a, Bjrn P. Meij a
a

Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3508 TD Utrecht, The Netherlands Department of Clinical Sciences, Division of Small Animals, Faculty of Veterinary Medicine and Animal Sciences, Swedish University of Agricultural Sciences, Ulls vg 12, Box 7040, 750 07 Uppsala, Sweden c Department of Pathobiology, Pathology Division, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3508 TD Utrecht, The Netherlands
b

a r t i c l e

i n f o

a b s t r a c t
Dogs can be grouped into two distinct types of breed based on the predisposition to chondrodystrophy, namely, non-chondrodystrophic (NCD) and chondrodystrophic (CD). In addition to a different process of endochondral ossication, NCD and CD breeds have different characteristics of intravertebral disc (IVD) degeneration and IVD degenerative diseases. The anatomy, physiology, histopathology, and biochemical and biomechanical characteristics of the healthy and degenerated IVD are discussed in the rst part of this two-part review. This second part describes the similarities and differences in the histopathological and biochemical characteristics of IVD degeneration in CD and NCD canine breeds and discusses relevant aetiological factors of IVD degeneration. 2012 Elsevier Ltd. All rights reserved.

Article history: Accepted 8 October 2012

Keywords: Intervertebral disc Degeneration Hernia Dog Chondrodystrophic Non-chondrodystrophic Notochordal cell

Introduction Intervertebral disc (IVD) degeneration can occur in all types of dog breeds, as described in Part 1 of this review (Bergknut et al., 2012d). Dog breeds can be classied into two groups on the basis of predisposition to chondrodystrophy, i.e. chondrodystrophic (CD) and non-chondrodystrophic (NCD). In addition to a distinctly different process of endochondral ossication, CD and NCD dogs are dissimilar with regard to the age of onset, frequency, and spinal location of IVD degeneration and IVD degenerative diseases, as rst described by Hansen (1952). IVD degeneration is more common in CD breeds, which are characterized by a disturbed endochondral ossication, primarily of the long bones, such that CD dogs have disproportionally short limbs (Hansen, 1952; Braund et al., 1975; Riser et al., 1980). Popular CD breeds include, among others, the (miniature) Dachshund, Basset Hound, French and English Bulldog, Shi Tzu, miniature Schnauzer, Pekingese, Beagle, Lhasa Apso, Bichon Fris, Tibetan Spaniel, Cavalier King Charles Spaniel, Welsh Corgi, and the American Cocker Spaniel (Hansen, 1952; Hoerlein, 1953; Goggin et al., 1970; Braund et al., 1975; Priester, 1976 ; Olby et al.,
Corresponding author. Tel.: +31 30 2538520.
1

E-mail address: L.A.Smolders@uu.nl (L.A. Smolders). These authors contributed equally to the work.

2004; Parker et al., 2009; Brisson, 2010; Bergknut et al., 2012a; Kranenburg et al., 2013). It should be noted that in the work by Hansen (1952), which provides the basis for the distinction between CD and NCD dogs, only the Dachshund, Dachsbrache, Pekingese, Spaniel (unspecied), and French Bulldog were classied as CD breeds. As it has not been established which short-legged dog breeds show the typical chondrodystrophy-related characteristics of IVD degeneration, studies are often inconsistent when classifying dog breeds as CD or NCD (Hansen, 1952; Hoerlein, 1953; Goggin et al., 1970; Braund et al., 1975; Priester, 1976; Olby et al., 2004; Parker et al., 2009; Brisson, 2010; Bergknut et al., 2012a; Kranenburg et al., 2013). In CD breeds, IVD degenerative disease typically develops around 37 years of age, with the degenerative disease mainly occurring in the cervical or thoracolumbar spine (Hansen, 1952; Hoerlein, 1953; Goggin et al., 1970; Priester, 1976; Olby et al., 2004; Brisson, 2010). In contrast, in NCD breeds IVD degenerative disease develops later, around 68 years of age, and mainly affects the caudal cervical or lumbosacral spine, although the thoracolumbar spine can also be affected (Hansen, 1952; Cudia and Duval, 1997; Macias et al., 2002; Cherrone et al., 2004; Brisson, 2010; Meij and Bergknut, 2010). NCD breeds frequently affected by IVD degenerative disease include the German Shepherd, Dobermann, Rottweiler, Labrador Retriever, Dalmatian, as well as mixed breed

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dogs (Cudia and Duval, 1997; Macias et al., 2002; Cherrone et al., 2004; Brisson, 2010; Meij and Bergknut, 2010; Bergknut et al., 2012a). Pathological ndings Chondrodystrophic dogs Histopathological differences between NCD and CD dogs can already be observed in the transition zone (TZ) of new-born dogs. Compared with the TZ of new-born NCD dogs, the TZ of newborn CD dogs is relatively wide, occupying most of the annulus brosus (AF), and its cells lack orientation (Hansen, 1952; Braund et al., 1975). In new-born NCD dogs, the transition from AF to nucleus pulposus (NP) is more distinct and abrupt (Hansen, 1952). IVD degeneration in CD breeds occurs earlier and faster than in NCD breeds (Hansen, 1952). In CD breeds, the change from a gelatinous, semi-uid NP to a drier NP (Fig. 1) can already be observed at 34 months of age (Hansen, 1952; Hoerlein, 1953; Braund et al., 1975; Ghosh et al., 1976b), and this transformation is complete in 75% of the cervical, 100%, of the thoracic, and 93.8% of the lumbar IVDs by 1 year of age. Ultimately, all IVDs are affected. In addition, the NP of CD dogs occupies a relatively small portion of the total transverse IVD surface and is located eccentrically to the dorsal side of the IVD (Hansen, 1952; Johnson et al., 2010). In contrast, the ventral TZ and AF are relatively wide compared to those of NCD dogs (Hansen, 1952; Braund et al., 1975; Ghosh et al., 1975; Johnson et al., 2010). These macroscopic differences in NP, TZ, and AF morphology decrease the functional size of the NP in IVDs from CD breeds (Adams et al., 1996). In CD dogs, at 3 months of age the NP is gradually replaced by chondrocyte-like cells embedded in a large amount of dense extracellular matrix (Hansen, 1952; Braund et al., 1975; Ghosh et al., 1975; Hunter et al., 2003; Cappello et al., 2006; Johnson et al., 2010; Bergknut et al., 2012b,c; Klauser et al., 2012). This chondroid metaplasia or chondrication of the NP tends to start in the periphery and spreads throughout the NP, and is completed in most IVDs by 1 year of age (Hansen, 1952). Notochordal cell remnants can however persist occasionally (Hansen, 1952; Braund et al., 1975; Ghosh et al., 1975; Gillett et al., 1988; Cappello et al., 2006; Johnson et al., 2010). Hansen (1952) termed this type of NP degeneration in CD breeds chondroid metamorphosis. The chondrocytelike cells have a high rate of apoptosis, which increases with age (Klauser et al., 2012). According to Hansen (1952), degeneration of the AF in CD dogs always occurs after NP degeneration and not independently. Typically, AF degeneration tends to occur at one specic location within the AF, where it is more severe and acute, resulting in more

pronounced disruption of the original IVD structure. Degenerative changes in the AF consist of chondroid metaplasia and partial or complete rupture and separation of the annular lamellae. These changes are most often observed in the dorsal AF and rarely in the ventral AF (Hansen, 1952; Bergknut et al., 2012b). Apart from this localized defect within the dorsal or dorsolateral AF, the AF may appear completely healthy (Hansen, 1952). IVD degeneration progresses rapidly in CD breeds and can result in dorsal herniation of the NP as early as 2 years of age (Hansen, 1952; Olby et al., 2004). Herniation typically has a sudden and explosive character, with complete rupture of the dorsomedian or dorsolateral AF, and dorsal longitudinal ligament, leading to extrusion of the degenerated NP into the vertebral canal (Hansen, 1952) (Fig. 2). This type of herniation, or Hansen type I herniation usually occurs in the cervical and thoracolumbar spine (Hansen, 1951, 1952; Olsson, 1951; Olsson and Hansen, 1952; Brisson, 2010), although Hansen type II herniation (discussed below) is also reported in CD breeds (Levine et al., 2006; Brisson, 2010; Kranenburg et al., 2013). The severity of chondrodystrophy seems to be associated with the risk of IVD herniation, as miniature Dachshunds are more frequently affected by IVD disease than normal-sized Dachshunds (Bergknut et al., 2012a). Non-chondrodystrophic dogs In NCD breeds, the macroscopic changes of the NP are largely similar to those in CD dogs, but typically occur later in life (>5 years) (Hansen, 1952; Braund et al., 1975). The transition from a gelatinous to brillar NP typically occurs in single IVDs and usually in the caudal cervical and lumbosacral spine (Hansen, 1952; da Costa et al., 2006; Meij and Bergknut, 2010). By 67 years of age, between 50% and 68.7% of all NPs have undergone such changes (in a subset of dogs consisting of various Terrier breeds, Toy breeds, Afganian, Alsatian, Boxer, Chow-Chow, Collie, Dalmatian, Dobermann pincher, Elkhound, Great Dane, Labrador, Maltese, Mongrel, New Foundland, Old English Sheepdog, Pointer, Poodle, Rottweiler, Russian Greyhound, Schnauzer, Setter, Spitz, St. Bernhard, Swedish Hound, and Whippet), but not all IVDs undergo degenerative change (Hansen, 1952, 1959). In NCD dogs, the notochordal cell remains the predominant cell type of the NP throughout life (Hansen, 1952, 1959; Braund et al., 1975; Cappello et al., 2006; Erwin et al., 2011; Johnson et al., 2010; Klauser et al., 2012), although age-related changes, which Hansen (1952) described as slow maturation (Fig. 3A), may occur. In this maturation process, collagenous strands connected to the TZ appear within the notochordal cell-rich NP, dividing the NP into distinct lobules of notochordal cells. The notochordal cells may undergo degenerative changes with a reduction in the size of the

Fig. 1. Transverse (left) and sagittal (right) sections through the L5L6 intervertebral disc of a 2-year-old chondrodystrophic dog, showing a dorsally located, drier nucleus pulposus (NP), a widened transition zone (TZ), and a normal annulus brosus (AF).

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suggest that the degenerative processes in CD and NCD dogs are more similar than previously assumed (Bergknut et al., 2012b,c; Kranenburg et al., 2013). Although CD and NCD dogs were characterized by chondroid and broid metamorphosis of the NP, respectively, Hansen (1952) emphasized that NCD and CD dogs showed many similarities regarding the fundamental processes involved in the degenerative cascade. In addition, Hansen described the broid metamorphosis of the NP in NCD dogs more as a process of maturation, rather than degeneration. Recent studies have shown that more advanced stages of NP degeneration in NCD dogs involve replacement of notochordal cells by chondrocyte-like cells, similar to the changes observed in CD dogs (Fig. 3D and F) (Hansen, 1952, 1959; Braund et al., 1975; Hunter et al., 2003; Cappello et al., 2006; Bergknut et al., 2012b,c; Kranenburg et al., 2013). This chondrication of the NP is also seen in other species. For example, studies on IVD degeneration in humans (naturally occuring) and mice (experimentally induced) showed the notochordal cell-rich NP to be sequentially transformed into a chondrocyte-like cell-rich NP with an increase in collagen II in the intercellular matrix (Yang et al., 2009; Bergknut et al., 2012c). Calcication
Fig. 2. Schematic pictures of a type I and type II herniation of an intervertebral disc (IVD). Type I IVD herniation involves complete rupture of the dorsomedian (left) or dorsolateral (right) annulus brosus (AF, grey) and dorsal longitudinal ligament (DLL, dark grey) with extrusion of degenerated nucleus pulposus (NP) material (yellow). Type I IVD herniation is commonly observed in chondrodystrophic dog breeds. Type II IVD herniation involves partial ruptures and disorganization of the AF (grey), and bulging of NP, AF, and DLL towards the dorsomedian (left) or dorsolateral (right) side. Type II IVD herniation is commonly observed in nonchondrodystrophic dog breeds.

intracellular vesicles and apoptosis (Kim et al., 2005), and acquire a more brocyte-like morphology. Hansen (1952) termed these morphological changes and the production of intracellular collagen bres broid metamorphosis (Fig. 3A, C, and E). However, more recent research suggests that the NP degenerative changes seen in NCD breeds are similar to those seen in CD breeds, i.e. chondrication of the notochordal cell-rich NP (Bergknut et al., 2012b,c; Kranenburg et al., 2013) rather than brosis of the NP (Fig. 3). The alleged distinction between broid and chondroid metamorphosis is discussed in greater detail below. The degenerative changes of the AF often occur concurrently with those of the NP (Hansen, 1952), but may occur earlier, before substantial changes in the NP are seen (Hansen, 1952). Degeneration is gradual in NCD breeds and mainly consists of partial rupture of the AF bres (Hansen, 1952), which can result in partial NP herniation through a defect in the AF, leading to intradisc protrusions (migration of NP into the AF) and bulging of the IVD and dorsal longitudinal ligament. This type of herniation is referred to as Hansen type II herniation (Fig. 2) and mainly occurs in the caudal cervical and lumbosacral spine (Hansen, 1951, 1952, 1959; Jones and Inzana, 2000; da Costa et al., 2006; Brisson, 2010; Meij and Bergknut, 2010). However, Hansen type I herniation can also occur in NCD dogs, mainly in the cervical and thoracolumbar spine (Cudia and Duval, 1997; Cherrone et al., 2004; Olby et al., 2004).

Chondroid vs. broid metamorphosis The Hansen (1952) classication of chondroid and broid metamorphosis has been the accepted histopathological distinction between CD and NCD breeds for the past 60 years (Fig. 3) (Hansen, 1952). However, diligent investigation of Hansens thesis and more recent studies using macroscopic grading schemes for IVD degeneration combined with histopathological grading

A process associated with IVD degeneration is calcication of the IVD, which is frequently observed in CD dogs, but rarely in NCD dogs (Fig. 4) (Hansen, 1952, 1959). Although most frequently found in the thoracic spine, IVD calcication can be found at all spinal levels (Hansen, 1952; Jensen and Ersboll, 2000; Jensen and Arnbjerg, 2001; Rohdin et al., 2010) and can be seen as early as 5 months of age; by 1 year of age 31.2% of cervical, 62.5% of thoracic, and 43.8% of lumbar IVDs in CD dogs show macroscopic signs of disc calcication (in a subset of dogs consisting of Dachshund, French Bulldog, Pekinese, Spaniel, and Dachsbrache) (Hansen, 1952, 1959). Although the prevalence of disc calcication increases with age (Hansen, 1952; Jensen and Arnbjerg, 2001), it appears to reach a steady state or maximum at 2427 months of age (Jensen and Arnbjerg, 2001). Calcication mainly occurs at the periphery of the NP and occasionally in the AF (Hansen, 1952; Stigen and Christensen, 1993), and can be observed before complete chondrication of the NP has occurred (Fig. 4C and D). NP calcication is thought to be dystrophic in nature secondary to tissue necrosis (Hansen, 1952; Melrose et al., 2009). It has been suggested that the mineral deposits found in the CD consist of hydroxyapatite (Melrose et al., 2009) but the actual composition of canine IVD mineralizations still needs to be elucidated. IVD calcication might be associated with IVD herniation (Stigen and Christensen, 1993; Stigen, 1996; Jensen and Christensen, 2000; Jensen and Arnbjerg, 2001; Jensen et al., 2008), with the total number of calcied discs in the spinal column being associated with the risk of developing IVD herniation at random spinal levels (not necessarily the calcied disc): the odds of IVD herniation occurring at any spinal location increases by 1.42 per calcied disc (Jensen et al., 2008). Although calcication can affect IVD integrity and calcied discs can herniate, calcication occurs more often than IVD herniation. Moreover, disc extrusion can occur in IVDs without any radiographic evidence of calcication (Hansen, 1952, 1959; Rohdin et al., 2010). Partial or complete resolution of disc calcication has been reported (Stigen, 1996; Jensen and Arnbjerg, 2001) and is common among CD dogs older than 3 years (Jensen and Arnbjerg, 2001). This might be because increased tension and tearing of the AF (with subsequent exposure of nuclear material to other tissues) may elicit an inammatory response, with calcied material being

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Fig. 3. (A and B) Original pictures from the thesis by Hansen (1952), depicting broid (A) and chondroid (B) metamorphosis of the nucleus pulposus. Original legends from the thesis: (A) Airedale Terrier, 10 years old. Nucleus pulposus from disc 9 (T3T4), showing vital cells with a certain similarity of brocytes (arrows) and an intercellular substance, rich in collagen bres (asterisks). Van Gieson, 400. (B) Dachshund, 4 months old. Nucleus pulposus of disc 2 (C3C4). Chondroid metamorphosis. The picture shows the denite cartilage-like cell pattern, except of one small group of a more original nuclear character. Van Gieson, 200. (CF) Original comparable pictures from Smolders et al. (2012): Haematoxylin & eosin (H&E) images of morphological changes in the nucleus pulposus (NP) of non-chondrodystrophic dogs. (C and E) show the socalled broid metamorphosis, the morphological picture of maturation or an early stage of degeneration of the NP, with an increase in brillar collagenous extracellular matrix (ECM, asterisks) dividing the NP into distinct islands of notochordal cells (NCs, arrows). The NCs decrease in size and show loss of intracellular vesicles and apoptosis. Note the morphological similarity of the cells in Hansens broid metamorphosis in (A) (arrows) with the notochordal cells in (C) (arrows), while these latter cells lack the typical morphological characteristics of brocytes. (D and F) show a later stage of degeneration with characteristic chondroid metaplasia of the NP, characterized by chondrocyte-like cells (arrowheads) and degeneration/apoptosis of NCs (dashed arrows). (E and F) are magnications of the squares in (C and D), respectively.

removed by macrophage-like cells (Jensen and Arnbjerg, 2001). Alternatively, pH changes within the IVD tissue may result in dissolution of calcied material. In particular, IVD degeneration is associated with a decrease in pH as a result of increased lactate production by the IVD cells (Urban et al., 2004). Acidosis has been shown to inhibit and resolve mineralization of extracellular matrix (Brandao-Burch et al., 2005) and as a result IVD degeneration can result in dissolution of calcied material. Biochemistry of the extracellular matrix of the intervertebral disc of CD and NCD dogs Proteoglycans Chondrication of the NP results in a signicant decrease in its proteoglycan and hyaluronic acid content (Ghosh et al., 1975; Bergknut et al., 2012b). At 9 months of age, the proteoglycan content of the NP is signicantly higher in NCD dogs than in CD dogs

(Fig. 5) (Ghosh et al., 1976b), whereas there are no differences in the proteoglycan content of the TZ and AF. The main glycosaminoglycan (GAG) of the NP, TZ, and AF is chondroitin sulfate (Ghosh et al., 1976b). At 30 months of age, the NP proteoglycan content decreases sharply in CD dogs, but remains constant throughout life in NCD dogs (Ghosh et al., 1977a,b). In particular, the proteoglycan content of the NP changes in CD dogs around 1 year of age, with a decrease in chondroitin sulfate and an increase in keratan sulfate, which ultimately replaces chondroitin sulfate (Ghosh et al., 1977a). These changes also occur in NCD dogs, but after 30 months of age and less extensively (Ghosh et al., 1977a,b). Differences in the proteoglycan concentration in the TZ and AF between the two categories of breeds are less pronounced (Ghosh et al., 1977a,b). Collagen Chondrication of the NP results in a signicant increase in collagen content (Ghosh et al., 1975, 1976a; Bergknut et al., 2012c).

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Fig. 4. Mid-sagittal (A) and transverse (B) sections of an intervertebral disc from a 2-year-old chondrodystrophic dog with extensive mineralization of the nucleus pulposus (arrowhead). (C) Transverse histological section (H&E) of the same intervertebral disc depicting the relatively normal structure of the ventral annulus brosus (AF) and a severely mineralized nucleus pulposus (purple). (D) Close-up view of the mineral deposits (purple).

Fig. 5. Schematic composition of the extracellular matrix of the nucleus pulposus in a 1-year-old non-chondrodystrophic (top) and chondrodystrophic (bottom) dog. The non-chondrodystrophic extracellular matrix contains long-chained proteoglycans rich in hyaluronic acid (HA; black line) and chondroitin sulfate (CS; light blue brushes), and it has a relatively low collagen content (grey bundles). The chondrodystrophic extracellular matrix contains signicantly more collagen (grey bundles), proteoglycan molecules are shorter, and shorter keratan sulfate (KS; dark blue) side chains replace the chondroitin sulfate side chains.

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Before 1 year of age, the NP at all spinal levels contains about 25% collagen in CD breeds but less than 5% in NCD breeds. The collagen content (percentage of total tissue) of the NP, AF and TZ in CD dogs is considerably greater than that in NCD dogs, and in CD dogs the collagen:non-collagenous protein ratio in the NP and AF increases sharply with age, starting before 1 year of age in the NP and at 30 months in the AF (Ghosh et al., 1976a). In contrast, the collagen content and the collagen:non-collagenous protein ratio remain relatively constant over time in NCD dogs, increasing later in life (60 months and 124 months, respectively) at particular spinal levels, such as L7S1. These changes are most probably due to chondrication/degeneration, with the NP of NCD breeds becoming more similar to that of CD breeds by 2130 months of age (Ghosh et al., 1976a). As the composition of the extracellular matrix depends on its constituent cells and on notochordal cells in particular (Cappello et al., 2006; Erwin et al., 2011), the observed differences in extracellular matrix composition in CD and NCD dogs probably reect the chondrication of the NP; chondricationoccurs in all IVDs in CD dogs and in selected IVDs in NCD dogs and give rise to rapid deterioration of the hydroelastic properties and, consequently, the hydraulic function of the IVD (Ghosh et al., 1976a,b, 1977a,b).

Aetiological factors for intervertebral disc degeneration The aetiology of IVD degeneration is multifactorial in both CD and NCD dogs; however, the early degeneration seen in CD (but not NCD) dogs suggests that there is a genetic component. Genes associated with the chondrodystrophic trait and with IVD degeneration and calcication have recently been identied, suggesting that IVD degeneration has a multigenetic aetiology (Hansen, 1952; Hoerlein, 1953; Braund et al., 1975; Stigen and Christensen, 1993). A locus on chromosome 12 has been shown to harbour genetic variations associated with IVD calcication in the Dachshund (Mogensen et al., 2011). In addition, the expression of a retrogene encoding broblast growth factor 4 (fgf4) located on chromosome 18 is strongly associated with chondrodystrophy in several CD breeds, including the Dachshund, Corgi, and Basset Hound (Parker et al., 2009). However, fgf4 retrogene expression was not found in several breeds commonly affected by accelerated IVD degeneration, such as the Beagle and American Cocker Spaniel (Parker et al., 2009). Therefore, different genetic factors appear to be at play in different breeds, which requires further investigation. CD and NCD dogs are different regarding the rotational biomechanics of the spine (Smolders et al., 2012). The difference in the spinal location of IVD degeneration between CD and NCD breeds, with IVD degeneration occurring throughout the spine in CD, but not NCD breeds (Hansen, 1952; Hoerlein, 1953; Braund et al., 1975) suggests that biomechanical factors inherent to individual spinal levels seem to be of less importance to IVD degeneration in CD dogs. Although it would seem plausible that the disproportionately long spine relative to the short legs of CD breeds might predispose them to IVD degeneration, no association has been found between IVD degeneration and spine length or other body dimensions such as leg length (Hansen, 1952; Jensen and Christensen, 2000). Moreover, the observation that degenerative IVD changes can already be found in newborn CD dogs supports the assumption that biomechanical factors are of minor importance in the development of IVD degeneration in CD dogs (Hansen, 1952; Braund et al., 1975). CD dogs with a relatively shorter spine, a greater height at the withers, and a large pelvic circumference have been shown to be at higher risk of IVD herniation (Levine et al., 2006), but body dimensions are not associated with IVD calcication (Jensen and

Ersboll, 2000). The greater susceptibility of the cervical and thoracolumbar spine to herniation in CD breeds was thought to be due to the transition from the rigid, thoracic spine to the more exible, lumbar spine. However, there is no convincing evidence to support this theory (Braund et al., 1977). The low risk of IVD displacement in the mid-thoracic spine (T1T9) may be due to the presence of the intercapital ligaments, which may prevent dorsal and dorsolateral displacement of the IVD (Hansen, 1952; Hoerlein, 1953). In NCD dogs, IVD degeneration commonly occurs at the caudal, cervical and lumbosacral spine, especially in large breeds (Hansen, 1952; Seiler et al., 2002; Rossi et al., 2004; da Costa et al., 2006). The anatomical conformation of the cervical spine in most dogs does not permit considerable axial rotation within each functional spinal unit. However, the more concave shape of the facet joints of the caudal cervical spine in large breeds compared with small breeds (Breit and Kunzel, 2002; Johnson et al., 2011) allows for considerable axial rotation and may contribute to instability and misalignment of the facets (Breit and Kunzel, 2002; Johnson et al., 2011), thereby increasing the workload and stresses on the cervical IVDs and promoting IVD degeneration (Farfan et al., 1970). The L7S1 junction of NCD dogs permits considerable mobility in exion/extension and axial rotation (Hansen, 1952; Benninger et al., 2006; Smolders et al., 2012). In addition, the L7S1 IVD in NCD dogs exhibits a low ventrodorsal shear stiffness, making it more susceptible for ventrodorsal subluxation/instability (Breit and Kunzel, 2001; Benninger et al., 2004, 2006). Moreover, there is an imbalance between the dimensions of the lumbosacral contact area (IVD and facet joints) and the bodyweight in large compared with small breeds (Breit and Kunzel, 2001), such that the L7S1 junction in large breeds may be subject to proportionally higher loads (Breit and Kunzel, 2001). These factors may predispose the L7S1 IVD to a high degree of wear and tear, leading to IVD degeneration. Of the NCD breeds, the German Shepherd dog (GSD), especially the male working dog, is at the highest risk of developing IVD degeneration and disease at L7S1 (Suwankong et al., 2008; Meij and Bergknut, 2010). In the GSD, the facet joint angle of L7S1 is more oblique (facet joint angle in the transverse plane) than those of L6L7 and L5L6 (Seiler et al., 2002; Rossi et al., 2004), whereas in other large breeds the facet joint angle is similar in L7S1 and adjacent segments (Seiler et al., 2002; Rossi et al., 2004). The oblique orientation of the L7S1 facet joint in relation to adjacent spinal segments causes a disproportionally high workload on the L7S1 IVD, predisposing the disc to degeneration, more so than in adjacent spinal segments (Farfan et al., 1970; Seiler et al., 2002; Rossi et al., 2004). An additional predisposing factor is lumbosacral transitional vertebra anomaly (LTVA), which is strongly associated with lumbosacral IVD degeneration in large breeds (e.g. the GSD) (Morgan et al., 1993; Fluckiger et al., 2006). Studies have shown that the mobility and distribution of force in the lumbosacral joints of dogs with LTVA is abnormal and that there is an increased translation in the IVD between the last lumbar vertebra and the LTVA (Fluckiger et al., 2006). These abnormal biomechanical characteristics may accelerate structural failure of the IVD (Morgan et al., 1993; Fluckiger et al., 2006). Lastly, the GSD is predisposed to sacral osteochondrosis, which involves degeneration and fragmentation of the sacral endplate (Lang and Hani, 1992; Hanna, 2001; Mathis et al., 2009). The abnormal shape of the sacral endplate may cause aberrant mechanical loading of the IVD, resulting in IVD degeneration. Alternatively, osteochondrosis of the sacral endplate may impede the supply of nutrients to the disc, predisposing it to degeneration (Lang and Hani, 1992; Hanna, 2001; Mathis et al., 2009).

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Conclusions The macroscopic, histopathological, and biochemical changes involved in IVD degeneration are largely similar in CD and NCD dogs, involving chondrication of the NP and structural failure of the IVD extracellular matrix. However, the age of onset, spinal level, progression of IVD degeneration, and the character of herniation are different, indicating that different aetiological factors are at play in the two breed types. In CD dogs, genetic factors related to the CD trait result in rapid IVD degeneration of all discs early in life, leading to progressive and then abrupt structural failure of the IVD, which in turn predisposes it to explosive type I herniation of NP material. In addition, calcication of the IVD is common in CD dogs. In NCD dogs, IVD degeneration occurs relatively infrequently, only at selected spinal levels, and mostly at old ages. As the NP matures, the notochordal cell population is preserved and although there are moderate histopathological changes, the extracellular matrix is healthy. At certain spinal levels, the IVD may be subjected to excessive stresses and loads, resulting in long-term wear and tear and subsequent IVD degeneration (chondroid metaplasia). This wear and tear process can result in structural failure and consequent bulging or type II herniation of the IVD. Conict of interest statement None of the authors of this paper has a nancial or personal relationship with other people or organizations that could inappropriately inuence 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. References
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