Review

Intervertebral disc degeneration in the dog. Part 2: Chondrodystrophic andnon-chondrodystrophic breeds

Lucas A. Smolders a,!,1, Niklas Bergknut a,b,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 Netherlandsb 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, Swedenc Department of Pathobiology, Pathology Division, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 108, 3508 TD Utrecht, The Netherlands

a r t i c l e i n f o

Article history:Accepted 8 October 2012

Keywords:Intervertebral discDegenerationHerniaDogChondrodystrophicNon-chondrodystrophicNotochordal cell

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 ofendochondral ossification, NCD and CD breeds have different characteristics of intravertebral disc (IVD)degeneration and IVD degenerative diseases. The anatomy, physiology, histopathology, and biochemicaland biomechanical characteristics of the healthy and degenerated IVD are discussed in the first part ofthis two-part review. This second part describes the similarities and differences in the histopathologicaland biochemical characteristics of IVD degeneration in CD and NCD canine breeds and discusses relevantaetiological factors of IVD degeneration.

! 2012 Elsevier Ltd. All rights reserved.

Introduction

Intervertebral disc (IVD) degeneration can occur in all types ofdog breeds, as described in Part 1 of this review (Bergknut et al.,2012d). Dog breeds can be classified into two groups on the basisof predisposition to chondrodystrophy, i.e. chondrodystrophic(CD) and non-chondrodystrophic (NCD). In addition to a distinctlydifferent process of endochondral ossification, CD and NCD dogsare dissimilar with regard to the age of onset, frequency, and spinallocation of IVD degeneration and IVD degenerative diseases, as firstdescribed by Hansen (1952).

IVD degeneration is more common in CD breeds, which arecharacterized by a disturbed endochondral ossification, primarilyof the long bones, such that CD dogs have disproportionally shortlimbs (Hansen, 1952; Braund et al., 1975; Riser et al., 1980). Popu-lar CD breeds include, among others, the (miniature) Dachshund,Basset Hound, French and English Bulldog, Shi Tzu, miniatureSchnauzer, Pekingese, Beagle, Lhasa Apso, Bichon Frisé, TibetanSpaniel, Cavalier King Charles Spaniel, Welsh Corgi, and theAmerican Cocker Spaniel (Hansen, 1952; Hoerlein, 1953; Gogginet 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).

It should be noted that in the work by Hansen (1952), whichprovides the basis for the distinction between CD and NCD dogs,only the Dachshund, Dachsbrache, Pekingese, Spaniel (unspeci-fied), and French Bulldog were classified as CD breeds. As it hasnot been established which short-legged dog breeds show the typ-ical ‘chondrodystrophy’-related characteristics of IVD degenera-tion, studies are often inconsistent when classifying dog breedsas 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 developsaround 3–7 years of age, with the degenerative disease mainlyoccurring 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 degenerativedisease develops later, around 6–8 years of age, and mainly affectsthe caudal cervical or lumbosacral spine, although the thoracolum-bar spine can also be affected (Hansen, 1952; Cudia and Duval,1997; Macias et al., 2002; Cherrone et al., 2004; Brisson, 2010; Meijand Bergknut, 2010). NCD breeds frequently affected by IVDdegenerative disease include the German Shepherd, Dobermann,Rottweiler, Labrador Retriever, Dalmatian, as well as mixed breed

1090-0233/$ - see front matter ! 2012 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tvjl.2012.10.011

! Corresponding author. Tel.: +31 30 2538520.E-mail address: L.A.Smolders@uu.nl (L.A. Smolders).

1 These authors contributed equally to the work.

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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 findings

Chondrodystrophic dogs

Histopathological differences between NCD and CD dogs can al-ready be observed in the transition zone (TZ) of new-born dogs.Compared with the TZ of new-born NCD dogs, the TZ of newbornCD dogs is relatively wide, occupying most of the annulus fibrosus(AF), and its cells lack orientation (Hansen, 1952; Braund et al.,1975). In new-born NCD dogs, the transition from AF to nucleuspulposus (NP) is more distinct and abrupt (Hansen, 1952).

IVD degeneration in CD breeds occurs earlier and faster than inNCD breeds (Hansen, 1952). In CD breeds, the change from a gelat-inous, semi-fluid NP to a drier NP (Fig. 1) can already be observedat 3–4 months of age (Hansen, 1952; Hoerlein, 1953; Braund et al.,1975; Ghosh et al., 1976b), and this transformation is complete in75% of the cervical, 100%, of the thoracic, and 93.8% of the lumbarIVDs by 1 year of age. Ultimately, all IVDs are affected. In addition,the NP of CD dogs occupies a relatively small portion of the totaltransverse IVD surface and is located eccentrically to the dorsalside of the IVD (Hansen, 1952; Johnson et al., 2010). In contrast,the ventral TZ and AF are relatively wide compared to those ofNCD 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 IVDsfrom CD breeds (Adams et al., 1996).

In CD dogs, at 3 months of age the NP is gradually replaced bychondrocyte-like cells embedded in a large amount of dense extra-cellular 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 chondroidmetaplasia or chondrification of the NP tends to start in the periph-ery and spreads throughout the NP, and is completed in most IVDsby 1 year of age (Hansen, 1952). Notochordal cell remnants canhowever 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 degen-eration in CD breeds chondroid metamorphosis. The chondrocyte-like 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 dogsalways occurs after NP degeneration and not independently.Typically, AF degeneration tends to occur at one specific locationwithin the AF, where it is more severe and acute, resulting in more

pronounced disruption of the original IVD structure. Degenerativechanges in the AF consist of chondroid metaplasia and partial orcomplete rupture and separation of the annular lamellae. Thesechanges are most often observed in the dorsal AF and rarely inthe ventral AF (Hansen, 1952; Bergknut et al., 2012b). Apart fromthis localized defect within the dorsal or dorsolateral AF, the AFmay appear completely healthy (Hansen, 1952).

IVD degeneration progresses rapidly in CD breeds and can resultin dorsal herniation of the NP as early as 2 years of age (Hansen,1952; Olby et al., 2004). Herniation typically has a sudden andexplosive character, with complete rupture of the dorsomedianor dorsolateral AF, and dorsal longitudinal ligament, leading toextrusion of the degenerated NP into the vertebral canal (Hansen,1952) (Fig. 2). This type of herniation, or Hansen type I herniationusually 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 alsoreported in CD breeds (Levine et al., 2006; Brisson, 2010;Kranenburg et al., 2013). The severity of chondrodystrophy seemsto be associated with the risk of IVD herniation, as miniatureDachshunds are more frequently affected by IVD disease thannormal-sized Dachshunds (Bergknut et al., 2012a).

Non-chondrodystrophic dogs

In NCD breeds, the macroscopic changes of the NP are largelysimilar to those in CD dogs, but typically occur later in life(>5 years) (Hansen, 1952; Braund et al., 1975). The transition froma gelatinous to fibrillar NP typically occurs in single IVDs and usu-ally in the caudal cervical and lumbosacral spine (Hansen, 1952; daCosta et al., 2006; Meij and Bergknut, 2010). By 6–7 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, Dober-mann pincher, Elkhound, Great Dane, Labrador, Maltese, Mongrel,New Foundland, Old English Sheepdog, Pointer, Poodle, Rottweiler,Russian Greyhound, Schnauzer, Setter, Spitz, St. Bernhard, SwedishHound, and Whippet), but not all IVDs undergo degenerativechange (Hansen, 1952, 1959).

In NCD dogs, the notochordal cell remains the predominant celltype 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 thismaturation process, collagenous strands connected to the TZappear within the notochordal cell-rich NP, dividing the NP intodistinct lobules of notochordal cells. The notochordal cells may un-dergo degenerative changes with a reduction in the size of the

Fig. 1. Transverse (left) and sagittal (right) sections through the L5–L6 intervertebral disc of a 2-year-old chondrodystrophic dog, showing a dorsally located, drier nucleuspulposus (NP), a widened transition zone (TZ), and a normal annulus fibrosus (AF).

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intracellular vesicles and apoptosis (Kim et al., 2005), and acquire amore fibrocyte-like morphology. Hansen (1952) termed these mor-phological changes and the production of intracellular collagenfibres ‘fibroid metamorphosis’ (Fig. 3A, C, and E). However, morerecent research suggests that the NP degenerative changes seenin NCD breeds are similar to those seen in CD breeds, i.e. chondri-fication of the notochordal cell-rich NP (Bergknut et al., 2012b,c;Kranenburg et al., 2013) rather than fibrosis of the NP (Fig. 3).The alleged distinction between ‘fibroid and chondroid metamor-phosis’ is discussed in greater detail below.

The degenerative changes of the AF often occur concurrentlywith those of the NP (Hansen, 1952), but may occur earlier, beforesubstantial changes in the NP are seen (Hansen, 1952). Degenera-tion is gradual in NCD breeds and mainly consists of partial ruptureof the AF fibres (Hansen, 1952), which can result in partial NP her-niation through a defect in the AF, leading to intradisc protrusions(migration of NP into the AF) and bulging of the IVD and dorsal lon-gitudinal ligament. This type of herniation is referred to as Hansentype II herniation (Fig. 2) and mainly occurs in the caudal cervicaland lumbosacral spine (Hansen, 1951, 1952, 1959; Jones andInzana, 2000; da Costa et al., 2006; Brisson, 2010; Meij andBergknut, 2010). However, Hansen type I herniation can also occurin NCD dogs, mainly in the cervical and thoracolumbar spine(Cudia and Duval, 1997; Cherrone et al., 2004; Olby et al., 2004).

Chondroid vs. fibroid metamorphosis

The Hansen (1952) classification of ‘chondroid’ and ‘fibroid’metamorphosis has been the accepted histopathological distinc-tion between CD and NCD breeds for the past 60 years (Fig. 3)(Hansen, 1952). However, diligent investigation of Hansen’s thesisand more recent studies using macroscopic grading schemes forIVD degeneration combined with histopathological grading

suggest that the degenerative processes in CD and NCD dogs aremore similar than previously assumed (Bergknut et al., 2012b,c;Kranenburg et al., 2013).

Although CD and NCD dogs were characterized by chondroidand fibroid metamorphosis of the NP, respectively, Hansen(1952) emphasized that NCD and CD dogs showed many similari-ties regarding the fundamental processes involved in the degener-ative cascade. In addition, Hansen described the fibroidmetamorphosis of the NP in NCD dogs more as a process of matu-ration, rather than degeneration.

Recent studies have shown that more advanced stages of NPdegeneration in NCD dogs involve replacement of notochordal cellsby chondrocyte-like cells, similar to the changes observed in CDdogs (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 chondrification of the NPis also seen in other species. For example, studies on IVD degener-ation in humans (naturally occuring) and mice (experimentallyinduced) showed the notochordal cell-rich NP to be sequentiallytransformed into a chondrocyte-like cell-rich NP with an increasein collagen II in the intercellular matrix (Yang et al., 2009; Bergknutet al., 2012c).

Calcification

A process associated with IVD degeneration is calcification ofthe IVD, which is frequently observed in CD dogs, but rarely inNCD dogs (Fig. 4) (Hansen, 1952, 1959). Although most frequentlyfound in the thoracic spine, IVD calcification can be found at allspinal levels (Hansen, 1952; Jensen and Ersboll, 2000; Jensen andArnbjerg, 2001; Rohdin et al., 2010) and can be seen as early as5 months of age; by 1 year of age 31.2% of cervical, 62.5% of tho-racic, and 43.8% of lumbar IVDs in CD dogs show macroscopic signsof disc calcification (in a subset of dogs consisting of Dachshund,French Bulldog, Pekinese, Spaniel, and Dachsbrache) (Hansen,1952, 1959). Although the prevalence of disc calcification increaseswith age (Hansen, 1952; Jensen and Arnbjerg, 2001), it appears toreach a steady state or maximum at 24–27 months of age (Jensenand Arnbjerg, 2001).

Calcification mainly occurs at the periphery of the NP and occa-sionally in the AF (Hansen, 1952; Stigen and Christensen, 1993),and can be observed before complete chondrification of the NPhas occurred (Fig. 4C and D). NP calcification is thought to bedystrophic in nature secondary to tissue necrosis (Hansen, 1952;Melrose et al., 2009). It has been suggested that the mineral depos-its found in the CD consist of hydroxyapatite (Melrose et al., 2009)but the actual composition of canine IVD mineralizations stillneeds to be elucidated.

IVD calcification might be associated with IVD herniation(Stigen and Christensen, 1993; Stigen, 1996; Jensen and Christen-sen, 2000; Jensen and Arnbjerg, 2001; Jensen et al., 2008), withthe total number of calcified discs in the spinal column beingassociated with the risk of developing IVD herniation at randomspinal levels (not necessarily the calcified disc): the odds of IVDherniation occurring at any spinal location increases by 1.42 percalcified disc (Jensen et al., 2008). Although calcification can affectIVD integrity and calcified discs can herniate, calcification occursmore often than IVD herniation. Moreover, disc extrusion can occurin IVDs without any radiographic evidence of calcification (Hansen,1952, 1959; Rohdin et al., 2010).

Partial or complete resolution of disc calcification has been re-ported (Stigen, 1996; Jensen and Arnbjerg, 2001) and is commonamong 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 inflammatory response, with calcified material being

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) ordorsolateral (right) annulus fibrosus (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 dogbreeds. Type II IVD herniation involves partial ruptures and disorganization of theAF (grey), and bulging of NP, AF, and DLL towards the dorsomedian (left) ordorsolateral (right) side. Type II IVD herniation is commonly observed in non-chondrodystrophic dog breeds.

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removed by macrophage-like cells (Jensen and Arnbjerg, 2001).Alternatively, pH changes within the IVD tissue may result in dis-solution of calcified material. In particular, IVD degeneration isassociated with a decrease in pH as a result of increased lactateproduction by the IVD cells (Urban et al., 2004). Acidosis has beenshown to inhibit and resolve mineralization of extracellular matrix(Brandao-Burch et al., 2005) and as a result IVD degeneration canresult in dissolution of calcified material.

Biochemistry of the extracellular matrix of the intervertebraldisc of CD and NCD dogs

Proteoglycans

Chondrification of the NP results in a significant decrease in itsproteoglycan and hyaluronic acid content (Ghosh et al., 1975;Bergknut et al., 2012b). At 9 months of age, the proteoglycan con-tent of the NP is significantly higher in NCD dogs than in CD dogs

(Fig. 5) (Ghosh et al., 1976b), whereas there are no differences inthe proteoglycan content of the TZ and AF. The main glycosamino-glycan (GAG) of the NP, TZ, and AF is chondroitin sulfate (Ghoshet al., 1976b). At 30 months of age, the NP proteoglycan content de-creases sharply in CD dogs, but remains constant throughout life inNCD dogs (Ghosh et al., 1977a,b). In particular, the proteoglycancontent of the NP changes in CD dogs around 1 year of age, witha 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 ageand less extensively (Ghosh et al., 1977a,b). Differences in the pro-teoglycan concentration in the TZ and AF between the two catego-ries of breeds are less pronounced (Ghosh et al., 1977a,b).

Collagen

Chondrification of the NP results in a significant increase in col-lagen content (Ghosh et al., 1975, 1976a; Bergknut et al., 2012c).

Fig. 3. (A and B) Original pictures from the thesis by Hansen (1952), depicting fibroid (A) and chondroid (B) metamorphosis of the nucleus pulposus. Original legends from thethesis: ‘(A) Airedale Terrier, 10 years old. Nucleus pulposus from disc 9 (T3–T4), showing vital cells with a certain similarity of fibrocytes (arrows) and an intercellularsubstance, rich in collagen fibres (asterisks). Van Gieson, 400!. (B) Dachshund, 4 months old. Nucleus pulposus of disc 2 (C3–C4). Chondroid metamorphosis. The pictureshows the definite cartilage-like cell pattern, except of one small group of a more original nuclear character. Van Gieson, 200!’. (C–F) Original comparable pictures fromSmolders 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 so-called fibroid metamorphosis, the morphological picture of maturation or an early stage of degeneration of the NP, with an increase in fibrillar collagenous extracellularmatrix (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 Hansen’s fibroid metamorphosis in (A) (arrows) with the notochordal cells in (C) (arrows), while these latter cells lack thetypical morphological characteristics of fibrocytes. (D and F) show a later stage of degeneration with characteristic chondroid metaplasia of the NP, characterized bychondrocyte-like cells (arrowheads) and degeneration/apoptosis of NCs (dashed arrows). (E and F) are magnifications of the squares in (C and D), respectively.

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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 fibrosus (AF) and aseverely 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. Thenon-chondrodystrophic extracellular matrix contains long-chained proteoglycans rich in hyaluronic acid (HA; black line) and chondroitin sulfate (CS; light blue brushes), andit has a relatively low collagen content (grey bundles). The chondrodystrophic extracellular matrix contains significantly more collagen (grey bundles), proteoglycanmolecules 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 collagencontent (percentage of total tissue) of the NP, AF and TZ in CD dogsis considerably greater than that in NCD dogs, and in CD dogs thecollagen:non-collagenous protein ratio in the NP and AF increasessharply with age, starting before 1 year of age in the NP and at30 months in the AF (Ghosh et al., 1976a). In contrast, the collagencontent and the collagen:non-collagenous protein ratio remain rel-atively constant over time in NCD dogs, increasing later in life(60 months and 124 months, respectively) at particular spinal lev-els, such as L7–S1. These changes are most probably due to chon-drification/degeneration, with the NP of NCD breeds becomingmore similar to that of CD breeds by 21–30 months of age (Ghoshet al., 1976a).

As the composition of the extracellular matrix depends on itsconstituent cells and on notochordal cells in particular (Cappelloet al., 2006; Erwin et al., 2011), the observed differences in extra-cellular matrix composition in CD and NCD dogs probably reflectthe chondrification of the NP; chondrificationoccurs in all IVDs inCD dogs and in selected IVDs in NCD dogs and give rise to rapiddeterioration 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 CDand NCD dogs; however, the early degeneration seen in CD (butnot NCD) dogs suggests that there is a genetic component. Genesassociated with the chondrodystrophic trait and with IVD degener-ation and calcification have recently been identified, suggestingthat 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 geneticvariations associated with IVD calcification in the Dachshund(Mogensen et al., 2011). In addition, the expression of a retrogeneencoding fibroblast growth factor 4 (fgf4) located on chromosome18 is strongly associated with chondrodystrophy in several CDbreeds, including the Dachshund, Corgi, and Basset Hound (Parkeret al., 2009). However, fgf4 retrogene expression was not found inseveral breeds commonly affected by accelerated IVD degenera-tion, such as the Beagle and American Cocker Spaniel (Parkeret al., 2009). Therefore, different genetic factors appear to be atplay in different breeds, which requires further investigation.

CD and NCD dogs are different regarding the rotational biome-chanics of the spine (Smolders et al., 2012). The difference in thespinal location of IVD degeneration between CD and NCD breeds,with IVD degeneration occurring throughout the spine in CD, butnot NCD breeds (Hansen, 1952; Hoerlein, 1953; Braund et al.,1975) suggests that biomechanical factors inherent to individualspinal levels seem to be of less importance to IVD degenerationin CD dogs. Although it would seem plausible that the dispropor-tionately long spine relative to the short legs of CD breeds mightpredispose them to IVD degeneration, no association has beenfound between IVD degeneration and spine length or other bodydimensions such as leg length (Hansen, 1952; Jensen andChristensen, 2000). Moreover, the observation that degenerativeIVD changes can already be found in newborn CD dogs supportsthe assumption that biomechanical factors are of minor impor-tance 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 thewithers, and a large pelvic circumference have been shown to beat higher risk of IVD herniation (Levine et al., 2006), but bodydimensions are not associated with IVD calcification (Jensen and

Ersboll, 2000). The greater susceptibility of the cervical and thora-columbar spine to herniation in CD breeds was thought to be dueto the transition from the rigid, thoracic spine to the more flexible,lumbar spine. However, there is no convincing evidence to supportthis theory (Braund et al., 1977). The low risk of IVD displacementin the mid-thoracic spine (T1–T9) may be due to the presenceof the intercapital ligaments, which may prevent dorsal anddorsolateral 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 Costaet al., 2006). The anatomical conformation of the cervical spinein most dogs does not permit considerable axial rotation withineach functional spinal unit. However, the more concave shapeof the facet joints of the caudal cervical spine in large breedscompared with small breeds (Breit and Kunzel, 2002; Johnsonet al., 2011) allows for considerable axial rotation and may con-tribute to instability and misalignment of the facets (Breit andKunzel, 2002; Johnson et al., 2011), thereby increasing the work-load and stresses on the cervical IVDs and promoting IVD degen-eration (Farfan et al., 1970).

The L7–S1 junction of NCD dogs permits considerable mobilityin flexion/extension and axial rotation (Hansen, 1952; Benningeret al., 2006; Smolders et al., 2012). In addition, the L7–S1 IVD inNCD dogs exhibits a low ventrodorsal shear stiffness, making itmore susceptible for ventrodorsal subluxation/instability (Breitand Kunzel, 2001; Benninger et al., 2004, 2006). Moreover, thereis an imbalance between the dimensions of the lumbosacral con-tact area (IVD and facet joints) and the bodyweight in large com-pared with small breeds (Breit and Kunzel, 2001), such that theL7–S1 junction in large breeds may be subject to proportionallyhigher loads (Breit and Kunzel, 2001). These factors may predis-pose the L7–S1 IVD to a high degree of wear and tear, leading toIVD degeneration.

Of the NCD breeds, the German Shepherd dog (GSD), especiallythe male working dog, is at the highest risk of developing IVDdegeneration and disease at L7–S1 (Suwankong et al., 2008; Meijand Bergknut, 2010). In the GSD, the facet joint angle of L7–S1 ismore oblique (facet joint angle in the transverse plane) than thoseof L6–L7 and L5–L6 (Seiler et al., 2002; Rossi et al., 2004), whereasin other large breeds the facet joint angle is similar in L7–S1 andadjacent segments (Seiler et al., 2002; Rossi et al., 2004). The obli-que orientation of the L7–S1 facet joint in relation to adjacentspinal segments causes a disproportionally high workload on theL7–S1 IVD, predisposing the disc to degeneration, more so thanin adjacent spinal segments (Farfan et al., 1970; Seiler et al.,2002; Rossi et al., 2004).

An additional predisposing factor is lumbosacral transitionalvertebra anomaly (LTVA), which is strongly associated with lumbo-sacral IVD degeneration in large breeds (e.g. the GSD) (Morganet al., 1993; Fluckiger et al., 2006). Studies have shown that themobility and distribution of force in the lumbosacral joints of dogswith LTVA is abnormal and that there is an increased translation inthe IVD between the last lumbar vertebra and the LTVA (Fluckigeret al., 2006). These abnormal biomechanical characteristics mayaccelerate structural failure of the IVD (Morgan et al., 1993;Fluckiger et al., 2006). Lastly, the GSD is predisposed to sacral oste-ochondrosis, which involves degeneration and fragmentation ofthe sacral endplate (Lang and Hani, 1992; Hanna, 2001; Mathiset al., 2009). The abnormal shape of the sacral endplate may causeaberrant mechanical loading of the IVD, resulting in IVD degener-ation. Alternatively, osteochondrosis of the sacral endplate mayimpede the supply of nutrients to the disc, predisposing it todegeneration (Lang and Hani, 1992; Hanna, 2001; Mathis et al.,2009).

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Conclusions

The macroscopic, histopathological, and biochemical changesinvolved in IVD degeneration are largely similar in CD and NCDdogs, involving chondrification of the NP and structural failure ofthe IVD extracellular matrix. However, the age of onset, spinal le-vel, progression of IVD degeneration, and the character of hernia-tion are different, indicating that different aetiological factors areat play in the two breed types.

In CD dogs, genetic factors related to the CD trait result in rapidIVD degeneration of all discs early in life, leading to progressiveand then abrupt structural failure of the IVD, which in turn predis-poses it to explosive type I herniation of NP material. In addition,calcification of the IVD is common in CD dogs. In NCD dogs, IVDdegeneration occurs relatively infrequently, only at selected spinallevels, and mostly at old ages. As the NP matures, the notochordalcell population is preserved and although there are moderate his-topathological changes, the extracellular matrix is healthy. At cer-tain spinal levels, the IVD may be subjected to excessive stressesand loads, resulting in long-term wear and tear and subsequentIVD degeneration (chondroid metaplasia). This wear and tear pro-cess can result in structural failure and consequent bulging or typeII herniation of the IVD.

Conflict of interest statement

None of the authors of this paper has a financial or personalrelationship with other people or organizations that could inappro-priately influence or bias the content of the paper.

Acknowledgments

The authors would like to thank the Multimedia Department ofthe Faculty of Veterinary Medicine, Utrecht University for theirtechnical assistance.

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