SPINE Volume 37, Number 5, pp 351–358 ©2012, Lippincott Williams & Wilkins BASIC SCIENCE The Dog as an Animal Model for Intervertebral Disc Degeneration? Niklas Bergknut, PhD,*† Joost P. H. J. Rutges, MD, PhD,‡ Hendrik-Jan C. Kranenburg, DVM,* Lucas A. Smolders, BSc,* Ragnvi Hagman, PhD,† Hendrik-Jan Smidt, BSc,* Anne-Sofie Lagerstedt, DVM, PhD,† Louis C. Penning, PhD,* George Voorhout, DVM, PhD,§ Herman A. W. Hazewinkel, DVM, PhD,* Guy C. M. Grinwis, PhD,¶ Laura B. Creemers, PhD,‡ Björn P. Meij, PhD,* and Wouter J. A. Dhert, MD, PhD*‡ Study Design. Prospective observational and analytic study. Objective. To investigate whether spontaneous intervertebral disc degeneration (IVDD) occurring in both chondrodystrophic (CD) and nonchondrodystrophic dogs (NCD) can be used as a valid translational model for human IVDD research. Summary of Background Data. Different animal models are used in IVDD research, but in most of these models IVDD is induced manually or chemically rather than occurring spontaneously. Methods. A total of 184 intervertebral discs (IVDs) from 19 dogs of different breeds were used. The extent of IVDD was evaluated by macroscopic grading, histopathology, glycosaminoglycan content, and matrix metalloproteinase 2 activity. Canine data were compared with human IVD data acquired in this study or from the literature. Results. Gross pathology of IVDD in both dog types (CD and NCD) and humans showed many similarities, but the cartilaginous endplates were significantly thicker and the subchondral cortices significantly thinner in humans than in dogs. Notochordal cells were still present in the IVDs of adult NCD but were not seen in the CD breeds or in humans. Signs of degeneration were seen in young dogs of CD breeds (<1 year of age), whereas this was only seen in older dogs of NCD breeds (5–7 years of age). The relative glycosaminoglycan content and metalloproteinase 2 activity in canine IVDD were similar to those in humans: metalloproteinase 2 From the *Department of Clinical Sciences of Companion Animals, Utrecht University, Utrecht, The Netherlands; †Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden; ‡Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands; §Division of Diagnostic Imaging, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands; and ¶Department of Pathobiology, Utrecht University, Utrecht, The Netherlands. Acknowledgment date: October 11, 2010. Revision date: March 25, 2011. Acceptance date: April 4, 2011. The manuscript submitted does not contain information about medical device(s)/drug(s). No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. Address correspondence and reprint requests to Niklas Bergknut, PhD, Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, PO Box 80.154, NL-3508 TD, Utrecht, The Netherlands; E-mail: n.bergknut@uu.nl DOI: 10.1097/BRS.0b013e31821e5665 Spine activity increased and glycosaminoglycan content decreased with increasing severity of IVDD. Conclusion. IVDD is similar in humans and dogs. Both CD and NCD breeds may therefore serve as models of spontaneous IVDD for human research. However, as with all animal models, it is important to recognize interspecies differences and, indeed, the intraspecies differences between CD and NCD breeds (early vs. late onset of IVDD, respectively) to develop an optimal canine model of human IVDD. Key words: intervertebral disc degeneration, spine, animal model, dog. Spine 2012;37:351–358 L ow back pain is a common disorder with a lifetime prevalence over 70% in the global population.1 It is the main cause of lost workdays in the United States, with estimated direct medical costs of $12 billion to $25 billion annually.2,3 Intervertebral disc degeneration (IVDD) and herniation are considered the main causes of acute and chronic low back pain.4–8 Before new treatments for IVDD are tested in clinical trials, their safety and functionality should be extensively tested in ex vivo and in vivo animal studies. Different animal models have been used in IVDD research,9–12 but in most of these models IVDD is induced manually or chemically rather than occurring spontaneously. Animal models of spontaneous IVDD are the sand rat,13–15 pintail mouse,16 baboon,17 and dog.18–20 Unlike mice and baboons, dogs commonly suffer from back pain due to IVDD and are diagnosed and treated for this. Moreover, the clinical presentation, macroscopic and microscopic appearance, diagnostics, and treatment of IVDD are similar in humans and dogs.8,21–23 Decompressive surgery and spinal fusion are common treatments for IVDD in both humans and dogs. In the dog, herniation of the intervertebral disc (IVD) is the most common cause of neurological deficits,24 and IVDDrelated diseases are common reasons for euthanasia in dogs younger than 10 years.25 The dog has frequently been used as a translational model for surgical procedures and biomechanical studies of the spine.26–31 In most of these studies, purpose-bred, research dogs have been used. However, the availability of veterinary IVDD patients as a study population for preclinical trials has not yet been utilized, although it is www.spinejournal.com Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 351 BASIC SCIENCE likely to be beneficial not only for humans but also for dogs as veterinary patients. Dogs can be divided into chondrodystrophic (CD) and nonchondrodystrophic (NCD) breeds based on their physical appearance. In CD breeds, endochondral ossification of the long bones is disrupted, resulting in short, bow-shaped extremities. This trait is strongly linked with IVDD and has in the past been favored in selective breeding for some breeds,24,32 such as dachshunds, with short legs and a high prevalence of IVDD. The disease is reported to develop by 1 year of age in CD breeds.32 However, NCD breeds, and especially large-breed dogs, also often develop IVDD-related diseases, but mostly later in life.24 The main factors responsible for IVDD are considered to be trauma or “wear and tear” in NCD breeds, but genetic in CD breeds.24,32 AIM OF THE STUDY To investigate whether spontaneous IVDD occurring in CD and NCD breeds can be used as valid translational models for human lumbar IVDD research, by comparing the morphological appearance, histological structure, and biochemical characteristics in different stages of IVDD in dogs and humans. MATERIALS AND METHODS Study Population and Processing of the Spines Lower spine segments from 19 dogs (of different breeds, ages, and sex) older than 1 year, without a history of IVDD-related diseases, that died or were euthanized for reasons unrelated to this study, were dissected within 24 hours postmortem. The spinal units (endplate-disc-endplate) of the lower spines were isolated, resulting in 184 intervertebral segments (137 from NCD and 47 from CD) and cut through the sagittal midline. The midsagittal plane of each spinal unit was subsequently photographed with a high-resolution digital camera (10 megapixels, Nikon, Tokyo, Japan) for gross morphological grading according to Thompson et al.33,34 Thereafter, 3- to 4-mm-thick midsagittal slices were cut and stored in 4% neutral-buffered formalin for histopathological examination. The remaining nucleus pulposus (NP) material was snap frozen (in 123 of the 184 IVDs) for glycosaminoglycan (GAG) analysis and matrix metalloproteinase 2 (MMP-2) zymography. Twenty-five histological sections (5 per Thompson grade) and 20 photographs (randomly selected) of adult human lumbar IVDs, collected with the permission of the Medical Ethics Committee, were obtained from the Biobank, Department of Pathology, University Medical Centre Utrecht. The age of the human specimens ranged between 3.3 and 88.5 years with a mean age of 56.2 years and a standard deviation of 24.9 years. Normal Anatomy and Gross Pathology All photographs were assessed by 3 independent observers (N.B., J.R., and B.M.) and graded I to V using the criteria of Thompson et al,34 which have been validated for use in dogs.33 The results were compared between human and canine IVDs as well as between CD and NCD. 352 www.spinejournal.com Dogs as Spontaneous IVDD Model • Bergknut et al The midsagittal photographs of all Thompson Grade I canine and human lumbar IVDs were used to measure the width (anterior-posterior), height (superior-inferior), and area of the midsagittal surface of the IVD and NP. All measurements were obtained using the software Image J (National Institutes of Health, Bethesda, MD). In the photographs of the canine IVDs, but not in those of the human IVDs, a transparent ruler was included to enable calculation of the dimensions. The dimensions (mm) of human lumbar IVDs were obtained from the literature.35–37 Ratios were calculated for IVD height/width, midsagittal NP area/IVD area, and NP width/ IVD width for all Thompson Grade I IVDs. Histopathology The midsagittal, intervertebral segments were fixed in 4% neutral-buffered formalin and decalcified in ethylenediaminetetraacetic acid. After decalcification, all discs were embedded in paraffin. With a microtome, 5-μm sections were cut, deparaffinized, and stained with hematoxylin/eosin or Alcian blue/ Picrosirius red.38 Thirty-five canine samples were used for histological evaluation: 7 samples of each Thompson grade were randomly selected (from CD and NCD pooled) and evaluated by 3 independent observers (N.B., J.R., and G.G.), using the modified Boos grading scheme recently described for use in dogs.39 The 3 observers also examined 25 human IVD sections (5 per Thompson grade) for comparison. The height of the entire IVD (superior-inferior) including endplates and the thickness and number of cell layers of each endplate were measured on histological sections of canine and human IVDs graded Thompson I. Glycosaminoglycan Assay The sulfated GAG content of 123 canine NP samples was measured using the Farndale (dimethylmethylene blue) assay.40 The relationship between GAG content and severity of degeneration in dogs was compared with that previously reported for humans.41,42 MMP-2 Zymography MMP-2 activity was assayed by gelatin zymography, as described previously.43 The protein content of the NP samples was measured44 to standardize the amount of tissue extract loaded onto precast gels (Bio-rad Laboratories, Hercules, CA) for the measurement of MMP-2 activity. High-resolution pictures were taken of the gels, in which the activity of the MMP-2 enzyme was shown as a clear band against a darker background. Enzyme activity was assessed by evaluating the amount of gel degraded by each individual NP sample.45 The background staining of each gel was used as baseline, and the relative destaining of the individual bands was calculated using Quantity One software (Bio-rad Laboratories Hercules, CA). MMP-2 activity was calculated and grouped per Thompson grade in the same way as for human IVD samples in a previous study.43 March 2012 Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. BASIC SCIENCE Statistical Analysis Differences between dogs and humans in the ratios of IVD height/width, NP area/IVD area, and NP width/IVD width of Thompson Grade I IVDs were analyzed by means of an independent sample t test. Normal distribution was verified through Q–Q plots. Pearson correlation test was used to evaluate the correlation between IVD dimensions and the weight/ size of the dogs and between GAG content and Thompson grades. A Mann-Whitney U test was used to test for the association between the type of dog and Thompson grades. Differences in GAG concentrations and MMP-2 activity between the 5 Thompson grades were analyzed by Kruskal–Wallis nonparametric 1-way analysis of variance with Bonferroni correction. Statistical significance was set at P < 0.05. RESULTS Normal Anatomy and Gross Pathology The overall appearance of the IVDs from humans and dogs was similar, with healthy IVDs from both species consisting of an annulus fibrosus (AF) with a clear lamellar structure and a gelatinous central NP. All 5 grades of IVDD described in humans by Thompson et al34 were also seen in dogs (Figure 1). However, growth plates were found in the intervertebral segments of the growing dogs (1 year old), which is not the case in growing humans.46 Dogs normally have 7 lumbar vertebrae in comparison with 5 in humans. The cartilaginous endplates were thicker in human IVDs, and, subsequently, more pronounced endplate irregularities were found in humans with Dogs as Spontaneous IVDD Model • Bergknut et al increasing severity of IVDD. In both dogs and humans, radial clefts and fissures in the NP parallel to the endplate were first detected in Thompson Grade III IVDD, whereas more extensive clefts and fissures, transecting the AF, were seen first in Thompson Grade IV IVDs in both humans and dogs. Although the canine IVDs were smaller than the human IVDs, the ratio of NP area/IVD area was similar in the 2 species (P = 0.18; Figure 1, Table 1); however, the ratios of IVD height/width, NP/IVD width, and endplate thickness/ IVD height were significantly different in healthy humans and dogs. As in humans, the height of the canine lumbosacral IVDs (5.4 ± 1.1 mm) was greater than that of the lumbar IVDs (3.5 ± 0.6 mm). IVD height at all spinal levels was significantly correlated with weight in dogs (r = 0.8, P = 0.01), as were IVD width and weight (r = 0.6, P = 0.01). The CD and NCD breed dogs were of comparable age (5.2 years for CD dogs and 5.5 years for NCD dogs). Higher Thompson grades (more degenerated IVDs) were seen more often in CD dogs than in NCD dogs (Z = −3.6, P = 0.0001; Table 2). There were too few human samples to allow analysis; however, the distribution of Thompson grades in the human IVDs was more similar to that of NCD dogs than to that of CD dogs (Table 2). Histopathology The overall histological appearance of the IVDs in different stages of degeneration was similar in humans and dogs (Figure 2): the AF and NP had a similar appearance, and the cell populations and density were comparable, with fibrocytelike cells in the AF and chondrocyte-like cells in the endplate and NP. Notochordal cells were present in the NP of 7/7 canine Grade I IVDs and in 2/7 Grade II IVDs. All IVDs containing notochordal cells were from NCD. Notochordal cells were not found in any IVDs from CD dogs or humans. In both humans and dogs, increasing Thompson grade was accompanied by degeneration of the NP with increasing cell cluster size, increasing disorganization of the AF lamellae, and increasing appearance of clefts and cracks in the IVD. However, the endplates had more chondrocyte layers in human IVDs than in canine IVDs, whereas subchondral bony cortices were found to be thicker relative to the total IVD height and endplate thickness in dogs than in humans. The absolute thickness of the subchondral bony cortices was comparable in the 2 species (Table 1). The pattern of Alcian blue/Picosirius red staining (staining GAG blue and collagen I red) was similar in human and canine IVDs: Thompson Grade I and II IVDs showed predominantly blue staining of the NP, whereas the NP of IVDs of Grade III or higher IVDs was stained red and blue or predominantly red. Glycosaminoglycan Assay A B Figure 1. Midsagittal images of (A) canine intervertebral discs and (B) human intervertebral discs depicting, from top to bottom, Thompson Grades I, II, III, IV, and V. Spine Because only 1 of the 123 canine IVD samples used for the GAG and MMP-2 analyses was Thompson grade V, it was grouped with the Thompson Grade IV IVDs for statistical analysis (Thompson IV+V). In dogs, the mean GAG concentrations in the NP (wet weight) were negatively correlated www.spinejournal.com Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 353 BASIC SCIENCE Dogs as Spontaneous IVDD Model • Bergknut et al TABLE 1. Measurements and Dimensions of the Midsagittal Surface of Canine and Human Lumbar Intervertebral Discs as Determined by Gross- and Histopathological Examinations Dog Measurement Human Mean ± SD Range Mean ± SD Range P 3.5 ± 0.6 2.4–4.7 10* 6–14* N/A Gross pathology Height IVD (mm) * * Width IVD (mm) 15.9 ± 2.0 11.0–18.9 35 27–45 N/A Ratio IVD height/width 0.22 ± 0.03 0.14–0.28 0.29 ± 0.05 0.23–0.34 <0.01† Ratio NP/IVD width 0.30 ± 0.05 0.21–0.41 0.38 ± 0.05 0.31–0.44 <0.01† Ratio NP/IVD area 0.25 ± 0.05 0.17–0.34 0.28 ± 0.02 0.24–0.31 0.18 Thickness EP (mm) 0.22 ± 0.06 0.1–0.42 1.58 ± 0.35 1.25–2.51 <0.01† EP thickness/IVD height (%) 6% 3%–11% 13% 9%–19% <0.01† 5 3–8 21 18–23 <0.01† 0.90 ± 0.36 0.27–1.78 0.66 ± 0.33 0.25–1.59 0.06 Histology Number of cell layers in EP Thickness cortex (mm) The P values reflect significant differences between the values obtained in dogs and humans. Only the ratios of the human IVDs could be obtained from the study material, whereas the actual measurements of human IVDs were all derived from the literature; hence, the SDs could only be calculated for the human IVD ratios and not for the actual measurements. IVD indicates intervertebral disc; NP, nucleus pulposus; EP, endplate; SD, standard deviation, N/A, not available. * Measurements obtained from the literature.35–37 †Statistically significant at P < 0.01. with increasing Thompson grades (r = −0.84, P = 0.0001; Figure 3), as has been reported in humans.41,42 MMP-2 Zymography The mean relative activity of MMP-2 in canine IVDs increased significantly with increasing Thompson grade over Grades I to III, but decreased in the group Thompson IV+V (Figure 4). A similar pattern has been reported in humans.43 DISCUSSION We found that the gross pathology, histopathology, GAG content, and MMP-2 activity of human and canine IVDs were TABLE 2. Distribution of Thompson Grades in the Intervertebral Discs From Humans and Chondrodystrophic (CD) and Nonchondrodystrophic (NCD) Dogs Thompson Grade CD (%) NCD (%) Humans (%) I 1 (2.1) 62 (45.3 7 (35 II 28 (59.6) 31 (22.6) 3 (15) III 10 (21.3) 28 (20.4) 3 (15) IV 4 (8.5) 12 (8.8) 4 (20) V 4 (8.5) 4 (2.9) 3 (15) 354 www.spinejournal.com similar in all different stages of IVDD. In addition, dogs are the only animals that develop IVDD-related diseases that are diagnosed and treated, both medically and surgically, in the same way as in humans. Combined, these facts indicate that canine IVDD could prove a suitable model of spontaneously occurring IVDD for human research. This study also shows the common occurrence of asymptomatic degenerated IVDs in dogs, just as in humans,47 and, in general, similar pathological changes were seen in degenerated IVDs from humans and dogs. Even the ratios of the different dimensions of the IVDs were similar in dogs and humans, although the canine IVDs were generally smaller relative to weight. Some differences were, however, found, such as the absence of growth plates in growing human vertebrae and the thicker cartilaginous endplates in humans. Whereas in dogs most vertebral growth takes place in the growth plates, in humans vertebral growth takes place in the junction between the vertebrae and the endplates,46 which may explain the thicker endplates found in humans. Also at the histological level, comparisons between dogs and humans revealed similar pathological changes due to degeneration. The hallmarks of IVDD, including chondroid cell clusters, disorganization of the AF, and increasing appearance of clefts and cracks, were found in dogs and humans with increasing severity of IVDD. Notochordal cells were found in the healthy IVDs of adult NCD dogs but not in the IVDs of adult humans or CD dogs; notochordal cells are present in the March 2012 Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. BASIC SCIENCE Figure 2. Midsagittal, hematoxylin/eosinstained histological sections of (A) canine intervertebral discs and (B) human intervertebral discs, depicting the histological appearance of, from top to bottom, Thompson Grades I, II, III, IV, and V. Dogs as Spontaneous IVDD Model • Bergknut et al A NP in children and CD dogs younger than 1 year.32,48 Apart from this discrepancy, the histological changes within each Thompson grade were similar in NCD and CD dog breeds and in humans, suggesting similar pathological processes. Also at the biochemical level, the changes occurring during IVDD were similar. In humans, MMP-2 activity is positively correlated with increasing Thompson grade up to Grade IV Spine B and decreases slightly in Grade V.43 We found a similar trend in dogs, with the exception that MMP-2 activity was already reduced in Grade IV+V degeneration. The GAG content in canine IVDs was negatively correlated with increasing Thompson grades, as previously described for human IVDD.41,42 Previous studies have shown that the GAG content of IVDs from CD dogs is lower than that of IVDs from www.spinejournal.com Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 355 BASIC SCIENCE Dogs as Spontaneous IVDD Model • Bergknut et al Figure 3. Box-plot displaying the glycosaminoglycan (GAG) concentration in the nucleus pulposus of canine intervertebral discs in relation to the Thompson Grade. *P < 0.05; z, outliers. NCD dogs of similar age.49,50 This is consistent with IVDD occurring at a lower age in CD than in NCD dogs. A previous study has also demonstrated the striking similarities between the magnetic resonance imaging appearance of IVDD in the different stages of degeneration in humans and dogs, even enabling the use of the human magnetic resonance imaging grading system for lumbar IVDD51 in veterinary practice.52 Pfirrmann grading of canine lumbar IVDD is strongly correlated with Thompson grades.33 In humans, degeneration of the IVD on T2-weighted magnetic resonance imaging is negatively correlated with the GAG content.53 Our results and those of previous canine studies33,52,54 indicate a similar trend in dogs, supporting the use of the dog as a translational model for studies of IVDD in humans. The fact that dogs walk on 4 legs and humans on 2 is often raised as a reason to not use dogs as models for human IVDD because it is believed that humans have higher axial loading on the spinal segments due to gravity. However, the axial loading patterns of human and canine IVDs have been shown to be comparable or even higher in dogs.30,55,56 The effect of IVDD on the biomechanical function of the canine spine has, however, not yet been investigated, and it would be of considerable interest to evaluate whether IVDD in dogs has similar effects on the functional spinal unit biomechanics as it does in humans. Figure 4. Box-plot displaying the matrix metalloproteinase 2 (MMP-2) activity in the nucleus pulposus of canine intervertebral discs in relation to the Thompson Grade. *P < 0.05; •, outliers. 356 www.spinejournal.com March 2012 Copyright © 2012 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. BASIC SCIENCE The gross morphological and histological appearances of IVDs in different stages of degeneration were similar in CD and NCD dogs, but IVDD manifested much earlier in CD dogs, as reported previously.24,32,57 All IVDs from adult CD dogs showed histological signs of degeneration, regardless of the dog’s age, whereas similar signs were found in only 54.7% of the NCD dogs and most often in older dogs. These findings support the theory that the etiology of IVDD is different in the 2 groups of dogs, which could thus make 2 different IVDD models: early (CD dogs) and late (NCD dogs) onset of IVDD. The IVDD commonly seen in CD dogs is believed to be of genetic origin, as all IVDs show signs of degeneration from an early age. In contrast, the IVDD seen in NCD dogs is more likely to be caused by “wear and tear,” as in most humans,22,24 although a genetic influence has also been suggested in some NCD breeds. This is supported by the higher correlation of age with IVDD in older NCD dogs and by the higher prevalence of IVDD in working dogs, and in the lumbosacral IVD, which is subjected to higher mechanical loads.58,59 Although IVDD in CD and NCD breeds appears to have different etiologies, the pathology is similar. When using the dog as a model for human IVDD research, it is important to recognize the differences between CD and NCD breeds (early vs. late onset, respectively). The fact that these 2 dog types spontaneously develop IVDD at vastly different ages makes them suitable as models for different types of studies. CD breeds, which develop degeneration in most of their IVDs early in life, are best suited for longitudinal studies investigating the process of IVDD, or for preclinical studies of interventional treatments aiming to prevent, stop, or slow the course of degeneration. NCD breeds, especially the German shepherd dog, are thought to have a similar disease process as humans with lumbosacral IVDD; that is, the degeneration of the lumbosacral disc in the German shepherd dog develops over a longer period (years) of chronic IVD stress, or “wear and tear.” These dogs would thus make suitable models for investigating the development of IVDD of the human lumbosacral disc, and here veterinary patients could also be used for preclinical studies of new treatments for IVD degenerative diseases. Relevant animal models are needed to improve the treatment of IVDD. As no animal model can perfectly mimic the complex processes of IVDD in humans,60 the similarities and differences between humans and animals should be considered when using animal models. Animal models of induced IVDD can result in substantial and reproducible IVDD in a short time, but it is likely that the pathological pathways differ from those involved in spontaneous IVDD, and thus the extrapolation of data from induced animal models to humans could lead to erroneous conclusions. This study has shown that the many similarities between canine and human IVDD could make the dog a suitable animal model of human IVDD. In addition, canine IVD material for research (ex vivo) is substantially easier to obtain than human. Another advantage with using dogs as an animal model is the potential of using veterinary IVDD patients as a study population for the investigation of mechanisms of degeneration and potential new treatments. This would reduce the use Spine Dogs as Spontaneous IVDD Model • Bergknut et al of laboratory animals as models of human disease and may also lead to better treatments for canine patients. These facts, together with our findings, suggest that the dog is one of the most appropriate animal models for spontaneous IVDD. CONCLUSIONS There are many similarities between IVDD in humans and in CD and NCD breeds, and both types of dog breeds could serve as animal models of spontaneous IVDD for human research. However, when employing the dog as a model for human IVDD research, it is important to recognize the specific interspecies differences as well as the difference of IVDD between CD and NCD dogs (early vs. late onset, respectively). ➢ Key Points ‰ Spontaneous IVDD is common in dogs and especially in CD breeds. ‰ The gross pathology and histology of IVDD showed many similarities in humans and dogs. ‰ MMP-2 activity is increased and GAG content is decreased with increasing severity of IVDD in both dogs and humans. ‰ The early/late onset of IVDD and early/late disappearance of notochordal cells in CD versus NCD dogs provide 2 different canine models of spontaneous IVDD. 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