INVITED REVIEW

A Review of the Pathogenesis of Canine Cranial Cruciate Ligament Disease as a Basis for Future Preventive Strategies Dominique J. Griffon1, DMV, PhD, Diplomate ECVS & ACVS 1

Department of Small Animal Surgery, Small Animal Clinic, University of Illinois, Urbana, IL

Corresponding Author Dominique J. Griffon, Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, 1008 West Hazelwood Drive, Urbana, IL 61802 E-mail: [email protected] Submitted April 2009 Accepted December 2009 DOI:10.1111/j.1532-950X.2010.00654.x

Cranial cruciate ligament (CCL) deficiency is the leading cause of lameness of the canine stifle and has important consequences in terms of morbidity and cost associated with its management. In spite of this impact, development of preventive strategies remains in its infancy, largely because of gaps in our understanding of the complex and likely multifactorial origin of CCL deficiency. The purpose of this article is to provide a critical review of the literature related to the pathogenesis of CCL deficiency and place this evidence in the context of potential preventive measures. Trauma accounts for a minority of CCL ruptures in dogs, whereas progressive degeneration of the ligament has been attributed to a variety of factors that may be broadly classified as genetic, conformational, environmental, immune-mediated, and inflammatory. Genetic screening appears promising as a long-term option in selected breeds while immunomodulating therapies may be implemented in the nearer future to reduce the incidence of contralateral disease in dogs with unilateral CCL deficiency. Preventive modification of conformation factors may be applicable to most breeds predisposed to CCL deficiency but requires further investigations into the relative contribution of individual factors, as well as into the feasibility, and potential risks of large-scale implementation.

Cranial cruciate ligament (CCL) deficiency is the leading cause of degenerative joint disease in the canine stifle.1–3 The economic impact of the management of this condition was estimated in 2003 to be US$1.32 billion annually, in the United States.4 The prevalence of CCL deficiency is increasing steadily and has more than doubled over the last 30 years.5 CCL deficiency commonly affects both stifles of large breed dogs, compounding the loss of function, and pain associated with the resulting instability.6 Contralateral CCL deficiency was predicted to occur within 5.5 months in !50% of Labradors.7 Tibial osteotomies have gained popularity to manage CCL deficiency, especially in large to giant dogs; however, these procedures have been associated with complications in 28–59% of cases, and their long-term superiority has not been established.8–10 In spite of the cost and morbidity associated with CCL deficiency and its management, research efforts aimed at developing preventive measures remain in their infancy. This gap is largely because of our limited understanding of the complex and likely multifactorial origin of CCL deficiency. Only 20% of canine CCL deficiency has been attributed to trauma.11 Instead, CCL deficiency in dogs is usually associated with a chronic history of progressive lameness consistent with a degenerative process. This review provides an updated and critical analysis of the literature related to the pathogenesis of nontraumatic CCL deficiency in dogs. Compared with previous

reports, emphasis will be on the causal relationship between conformation factors and CCL deficiency. Potential strategies for future investigations and eventual prevention of CCL deficiency are suggested.

INFLUENCE OF GENETICS The rationale behind exploring the genetic component of cranial cruciate ligament disease (CCLD) is based on the well-established breed predisposition for nontraumatic CCL deficiency in dogs. Dogs have traditionally been considered as predisposed or protected against the disease by comparing the relative incidence of CCL deficiency and odds ratio (OR) between breeds.12,13 This data has been especially relevant to studies dealing with causative factors of CCL deficiency, as it has been applied to select normal controls and predisposed groups. Breeds with high OR for CCL deficiency include Labrador Retrievers (OR: 2.56–5.05), Rottweilers (3.58–6.92), and Newfoundlands (3.77–6.65) whereas Greyhounds (0.55) have consistently been reported at low risk for the disease.12,13 The only investigations into the genetics of CCLD in dogs consequently focused on a population of 574 Newfoundlands.14 The authors reported a prevalence for CCL deficiency of 22%, and proposed a recessive mode of inheritance, with 51% penetrance. Four microsatellite markers located on 4

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Genotype Skeletal conformation of the limb

Muscle conformation

Conformation of the knee Dominance of the quadriceps Femoral angulation / torsion and / or gastrocnemius over the Tibial angulation / torsion hamstring muscle MPL Proximal angulation of the tibia Excellive TPA Alignment of the patellar tendon ICN stenosis Cyclic loading of the CCL Exercise

Obesity Arthritis

Degeneration of the CCL

Figure 1 Factors implicated in the pathogenesis of CCLD and their potential interrelationship. Genetics may have a direct influence on the structural properties of the CCL (dashed arrow) or influence other factors contributing to CCLD. TPA, tibial plateau angle; MPL, medial patellar luxation; ICN, intercondylar notch stenosis; CCLD, cranial cruciate ligament disease.

chromosomes were consequently associated with CCL deficiency in a subset of 90 Newfoundlands.15 In spite of the particularly high prevalence and OR in that breed, only 27% of the phenotypic expression of CCLD in these dogs was attributable to genetics, whereas 73% was linked to environmental factors.14 Whether genetics exert a direct influence on the structural properties of the CCL or control conformation factors that lead to CCL deficiency remains unclear (Fig 1). Together, these findings suggest that the identification of gene markers will warrant long-term research efforts but may contribute to the control of CCL deficiency in selected breeds.

CONFORMATION OF THE PELVIC LIMB Poor conformation of the pelvic limb such as genu varum (Fig 2) or a ‘‘straight’’ stance may lead to misalignment of

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the joints and exacerbate the degenerative process predisposing to early CCL rupture.11,13,16 These claims were initially prompted by clinical observations and have not been well substantiated, largely because of their inconsistent presence in dogs with CCL deficiency, their variability, and difficulties in obtaining objective measurements. Among these, pelvic limbs with a bowlegged (genu varum) appearance are believed to be prone to CCL deficiency because of an excessive internal rotation of the tibia.11 Genu varum often combine poor coxofemoral conformation (dysplasia) with femoral angulation and internal rotation of the tibia. This conformation has been associated with other conditions, such as proximal angulation of the tibia and medial patellar luxation, both of which are believed to increase the stress placed on the CCL.11,17 Stifles with medial patellar luxation are predisposed to CCL deficiency because the patellar tendon is medially displaced and no longer acts as a restraint to the cranial tibial thrust (CTT).11,18 In addition, the force exerted by the extensor mechanism is no longer aligned with the long axis of the femur. Contraction of the quadriceps during stifle extension therefore forces the tibia in internal rotation, generating a force primarily counteracted by the CCL. The alignment of the extensor mechanism can be evaluated using advanced imaging techniques to measure the quadriceps angle.19 The quadriceps angle (QA) correlates with the degree of patellar luxation19,20 but did not differ in Labrador Retrievers with or without CCL deficiency.21 This mechanism is therefore unlikely to contribute to the pathogenesis of CCL deficiency in dogs that are not concurrently affected by medial patellar luxation. The degree of femoral angulation associated with a bowlegged conformation has traditionally been assessed by measuring the deviation of the mechanical and/or anatomic axis of the femur on ventrodorsal radiographs of the pelvis (Fig 2). This technique has been found reliable in normal cadavers with correct positioning,22 but is subject to false positive in dogs with limited hip extension. Horizontal beam projections of the femur or computed tomography (CT) (Fig 2) are both suitable alternatives in these

Figure 2 Cranial cruciate ligament deficiency, hip dysplasia and medial patellar luxation in a dog with genu varum. Appearance on physical examination (A), radiographs (B), and computed tomography (C) of the pelvic limbs.

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instances. Medial deviation of the mechanical axis of the femur, reaching up to 101, was measured on a retrospective review of ventrodorsal radiographs in normal dogs with excellent hip conformation.23 Interestingly, this deviation was greater (by 31) in Labrador Retrievers, Golden Retrievers, and Rottweilers compared with German Shepherds. We recently reported a similar degree of femoral angulation in Labradors Retrievers with or without CCLD (7 # 41 in varus) suggesting that varus deformation of the femur is unlikely to contribute to the development of CCLD in this breed.21 However, we unexpectedly identified a greater degree of internal femoral torsion on CT of diseased as well as contralateral limbs. The torsion seemed located distal to the lesser trochanter, rather than at the level of the femoral neck. Deformation of the distal femur may alter the relationship between femoral and tibial articular surfaces, increasing rotational forces placed on the CCL. Although the impact of this deformation warrants further investigation, internal rotation of the femoral condyles could also affect the relationship between the proximal aspect of the CCL and the intercondylar notch, leading to impingement of the ligament during extension of the stifle. Independently of femoral angulation and genu varum, malalignment of the tibia has also been incriminated in the pathogenesis of CCL deficiency.11,24 Tibial deformity may lead to cranial displacement of the tibia in relation with the femur, greater rotational forces and/or hyperextension of the stifle, generally increasing the stress placed on the CCL during weight bearing.11 However, the proposed influence of varus deformity of the proximal tibia on CCL deficiency24 was not confirmed in a subsequent radiographic study of dogs with and without CCL deficiency.25 Evaluating the causative effect of internal rotation of the tibia on CCL deficiency is complicated by the risk of artifacts associated with radiographic methods of measurements. Indeed, the linear displacement of the medial border of the calcaneus on a caudocranial projection does not distinguish internal torsion resulting from an anatomic malformation or from malpositioning.26 Rotational malpositioning of the tibia may also occur without concurrent rotation of the femur because CCLD results in an increased range of internal rotation.27 Although limbs affected with CCL deficiency had a greater degree of internal tibial rotation than normal limbs on radiographs, this result was not confirmed by CT in our recent study.21 These findings confirm the previously reported superiority of CT when evaluating tibial torsion and do not support a causal relationship between tibial torsion and CCL deficiency.26 However, they raise the question of rotational instability secondary to CCL deficiency and the potential need to address this issue concurrently with elimination of cranial tibial translation.

CONFORMATION OF THE STIFLE Conformation of the Intercondylar Notch (ICN) Impingement on a narrow ICN as a cause of CCLD in dogs is a concept derived from the human literature. In man,

Pathogenesis of Canine Cranial Cruciate Ligament Disease

CdCL

Figure 3 Arthroscopic appearance of a narrowed intercondylar notch in a dog with complete cranial cruciate ligament (CCL) rupture and secondary degenerative joint disease. Stenosis of the cranial outlet of the intercondylar notch (block arrows) may cause primary or secondary impingement of the CCL. CdCL, caudal cruciate ligament.

congenital stenosis of the intercondylar fossa is believed to account for 2–4% of anterior cruciate ligament (ACL) rupture, typically affecting both knees of younger patients without major trauma.28 Several studies have also reported the presence of a narrow ICN in athletes predisposed to ACL disease.29,30 In normal canine knees, the ICN is oriented 121 from the dorsal plane of the femoral diaphysis and obliqued 71 in a proximolateral to distomedial direction.31 The CCL is believed to contact the caudal outlet of the ICN at about 1151 of stifle extension, the point of contact reaching the cranial extent of the fossa at 1551 of extension. Several studies support the presence of a narrowed ICN in dogs with CCL deficiency (Fig 3), potentially leading to impingement from the medial aspect of the lateral femoral condyle, or at the level of the intercondylar roof of the fossa.32,33 However, the retrospective nature of these studies prevents their ability to differentiate ICN as a cause of CCL deficiency or as a secondary change to chronic CCL insufficiency and degenerative joint disease. The dimensions of the ICN were recently found greater in stifles harvested from Greyhounds (rarely affected by CCL deficiency) than in 2 breeds predisposed to CCL deficiency (Labrador and Golden Retrievers).34 This inherently narrower ICN in predisposed breeds would increase the risk of chronic impingement of the CCL, eventually leading to its degeneration and rupture. Interestingly, the authors found some evidence of fibrocartilaginous metaplasia in areas of impingement of the CCL in breeds at risk for CCL deficiency. Although this finding was associated with hyperexpression of a degradative enzyme, collagen levels were similar in all groups. Whereas this provides the strongest evidence of a potential contribution of ICN stenosis to the pathogenesis of CCLD, the authors did not analyze areas of the CCL that were not subjected to impingement against the notch within each dog.

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These findings could therefore be attributed to breed differences in terms of anatomy, composition, and metabolism that may not necessarily relate to CCL deficiency. In addition, this proposed mechanism of weakening of the CCL is unlikely to translate into preventive measures. Indeed, refilling of the notch occurred within 6 months after notchplasty in an experimental study of dogs with normal or unstable knees, and was more pronounced in diseased stifles.35,36 Notchplasty is therefore unlikely to prevent stenosis and impingement of the CCL in stifles with inherently narrow ICN or those with early CCLD. Conformation of the Proximal Aspect of the Tibia The relationship between the conformation of the proximal aspect of the tibia and the pathogenesis of CCL deficiency stems from a biomechanical model developed by Slocum.37 According to this model, ground reaction forces generated during the stance phase are transmitted along the tibial axis and a shear force or CTT is generated by the compression of the femur against a caudally oriented tibial plateau slope. This femorotibial shear force is therefore partly oriented in the cranial direction, leading to cranial translation of the tibia. In a stable stifle, this force is opposed by a combination of static (primarily CCL and menisci) and active (primarily hamstring muscle) stabilizers (Fig 4). The magnitude of this force generated by contraction of the gastrocnemius muscle depends on the amplitude of the compressive force (70% of the body weight at trot) but also on the slope of the tibial plateau with respect to the axis joining the centers of motion of the stifle and hock.37,38 This theory provided a basis for the tibial plateau leveling osteotomy (TPLO), a procedure that is not aimed at restoring the anatomical stability of the CCL deficient stifle, but modifies the joint geometry to neutralize CTT during weight bearing.38 Although this procedure has gained tremendous popularity for treatment of CCL deficiency in large breed dogs, the correlation between the steepness of the tibial plateau and the development of CCL deficiency remains controversial, especially in Labrador Retrievers.8,39,40 Morris and Lipowitz41 measured greater tibial plateau angle (TPA) in diseased stifles in a mixed population of dogs with CCL deficiency compared with a normal group. Similar findings were identified in contralateral stifles of affected dogs, thereby strengthening the evidence of a contribution of TPA to the pathogenesis of CCL deficiency. Indeed, these stifles may be considered as predisposed, based on the incidence (37%) of contralateral disease in dogs with CCL deficiency.6 Labrador Retrievers have a steeper TPA (25.6 # 0.61) than Greyhounds (22.5 # 0.81), but no difference was found between Labrador Retrievers with (23.5 # 3.11) and without CCL deficiency (27.97 # 0.71,40 23.6 # 3.5139). TPA measured on dogs in a standing position was similar between Greyhounds and normal Labradors, eliminating differences in standing angles as a confounding factor.40 However, these findings illustrate the difficulty differentiating interbreed variations from a causal relationship with CCL deficiency. We recently

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Figure 4 Schematic representation of forces acting on the stifle joint. The cranial tibial thrust (CTT) created during the stance phase of the gait is generated by contraction of the gastrocnemius muscle and counteracted by active (flexor muscles) and passive (menisci and CCL) restraints. The direction of the craniocaudal shear generated by the contraction of the quadriceps muscle is influenced by the degree of flexion of the stifle and the position of the patellar tendon with respect to the tibial plateau. CCL, cranial cruciate ligament.

reported steeper TPAs in affected (28.1 # 3.41), but not in contralateral stifles (27.7 # 3.01) of Labrador Retrievers with CCL deficiency compared with normal dogs (25.2 # 3.31) of the same breed.21 The discrepancy between studies most likely results from interbreed variations, differences in selection criteria for normal dogs, and the variable inclusion of dogs with excessive TPAs among study groups. In a retrospective review of dogs with CCL deficiency using predictive 3-dimensional modeling of the tibia, excessive tibial slope ( 4 301) correlates strongly with a cranial angulation of the proximal tibia (Fig 5).42 The association between CCL deficiency and a deformity of the proximal tibia had previously been noted in several clinical reports.17,43,44 A greater inclination of the proximal tibia in relation to its distal axis (DTA/PTA) was confirmed in CCL deficiency limbs of Labrador Retrievers.21 This same angulation was found in sound, contralateral limbs compared with normal controls providing additional evidence to support the role of this deformity in the pathogenesis of CCLD. Based on these 2 studies, DTA/PTA angles 4 101 (91 in

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Pathogenesis of Canine Cranial Cruciate Ligament Disease

DTA/PTA angle

PTA

Figure 5 Proximal deformity of the tibia as a cause of excessive tibial plateau angle and cranial cruciate ligament disease (CCLD). The radiograph on the left illustrates an example of a Labrador with a deviation of the axis of the proximal tibia (PTA) 4 91 relative to the distal axis of the tibia (DTA) and a tibial slope of 361. The radiograph on the right was obtained on a Labrador with CCLD, a tibial plateau slope and alignment of the proximal tibia within normal range.

of 58 dogs with CCLD and a tibial slope of at least 351.45 Compared with their controls (CCL deficiency dogs with a maximum TPA of 301), case dogs were 3 times more likely to have been neutered before they reached the age of 6 months. Early gonadectomy may prolong the growth of the cranial proximal tibial physis, since it has been found to delay physeal closure and increase longitudinal bone growth.46 Alternatively, delayed physeal closure induces histologic changes that may predispose the physis to injury and premature closure of the caudal tibial physis.46–48 Regardless of its origin, excessive tibial plateau slope and cranial angulation of the tibia seem to characterize a subpopulation of dogs that may benefit from specific therapeutic options and early preventive measures. Options for prevention of CCL deficiency in these dogs include a corrective tibial osteotomy at maturity and epiphysiodesis of the cranial tibial growth plate in immature dogs.49 Further investigations are required to limit the morbidity and verify the preventive effects of these procedures. In addition, the second strategy relies on the ability to predict adult TPAs based on measurements obtained at an early age. In a longitudinal study of 10 Labrador Retrievers and 20 Labrador Retriever-hound dogs, TPA could be measured accurately after 90 days of age, while landmarks were difficult to identify and resulted in falsely low measurements in younger puppies.50 The tibial plateau slope did not change from 90 days of age to physeal maturity, potentially allowing early detection of premature physeal closures. However, none of the dogs included in this study seemed to develop excessive TPAs and the alignment of the proximal tibia was not evaluated. Whereas these results are encouraging, determining the age at which excessive TPA and tibial deformity can be predicted is a prerequisite to establishing screening and preventive programs in breeds predisposed to these types of skeletal conformation.

Alignment of the Patellar Tendon 21

42

Mostafa et al, 11.21 in Osmond et al ) are consistent with cranial bowing of the proximal tibial shaft, and may be considered as a risk factor for steep TPA and CCL deficiency. This deformity was identified in 9% of a mixed population42 and 33% of Labrador Retrievers with CCL deficiency,21 suggesting that its incidence may vary between breeds. The causal relationship between a cranial angulation of the proximal tibia and CCL deficiency has been attributed to a premature closure of the caudal portion of the tibial growth plate and/or an increased growth of the cranial aspect of the tibial physis. Both mechanisms would increase the steepness of the tibial plateau, thereby leading to failure of its passive restraint, the CCL. However, the origin of this disturbance of the proximal tibial growth plate remains unclear. Microtrauma, imbalance between the quadriceps and gastrocnemius muscles, reduced blood flow to the caudal physis and increased vascularity to the cranial physis have all been proposed to explain this developmental anomaly.17,43,44 The only investigation of risk factors for excessive TPA consists of a case–control study

The role of the patellar tendon in the biomechanics of the knee was emphasized in a model derived from a cadaveric study in humans, in which joint reaction forces were identical to those generated along the patellar tendon.51 Based on these findings, Montavon proposed that joint reaction forces were aligned with the patellar tendon, rather than the tibial axis.52 This model therefore differs from the biomechanical basis of TPLO.53 Regardless of the alignment of the ground reaction force, the role of the extensor mechanism must be considered in any realistic biomechanical model of the stifle as its intervention is required to maintain stifle extension during the stance phase. The patella acts as a pulley, determining the alignment of the force generated by contraction of the quadriceps. This force is necessarily distributed along the patellar ligament, thereby generating a craniocaudal femorotibial shear force. The magnitude and direction of this force depend on the inclination of the patellar tendon angle (PTA) with regards to the joint surface, defined as the axis of the tibial plateau or the common tangent to the tibiofemoral contact point. The PTA

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increases with stifle extension and CTT is generated once this angle exceeds a crossover of 90 # 9.01 (Fig 4).53,54 A tibial tuberosity advancement (TTA) procedure was developed to move the point of insertion of the quadriceps cranially and maintain a PTA to a maximum of 901 at full joint extension during weight bearing.52,55,56 This angle was fixed at 1351 of extension, which is typically considered as the average standing angle of the canine stifle. However, several kinematic studies report a degree of stifle extension exceeding 1501 at the beginning of the stance phase.57–59 Based on our personal kinematic studies, the maximum degree of stifle extension during the stance phase of Labrador Retrievers at the trot was 1511 ( # 7) in CCL deficient limbs, 1481 ( # 7) in contralateral limbs and 1541 ( # 7) in normal limbs. TTA has recently been found to neutralize CTT in cadaveric pelvic limbs tested at 1351 of extension,55 but the clinical relevance of any remaining CTT during full extension has not been addressed. Clinical improvement after tibial osteotomies does not necessarily imply a causal relationship between the skeletal characteristic corrected by the procedure and CCL deficiency. In fact, TPLO and TTA illustrate how similar goals (control of the CTT) may be achieved by altering different structures of the knee.53 Instead, the inclination of the patellar tendon was first proposed as a factor contributing to the pathogenesis of CCL deficiency based on a comparison of the PLA in 54 dogs with partial CCL deficiency and 9 normal cadaveric specimen.60 The axis of the femur was extrapolated to determine the degree of stifle flexion on radiographs of live dogs and regression equations applied to account for the great variability in radiographic positioning (incidental flexion angles ranging from 441–1321). In spite of these limitations, the angle between the patellar tendon and the tibial plateau or the tangent to the femorotibial point of contact was increased in diseased stifles by 51 and 21, respectively. As a result, dogs with CCL deficiency would be expected to generate more cranial shear during mobilization of the quadriceps muscle. In addition, the degree of stifle flexion required to eliminate the cranial tibiofemoral shear was 101 greater in dogs with CCL deficiency. These findings prompted the authors to conclude that dogs with CCL deficiency hold the affected limb in flexion to avoid loading of the limb in a position exceeding the crossover angle. They also suggested that dogs with a ‘‘straight’’ conformation of the pelvic limb may be predisposed to CCL deficiency because they maintain their stifles in a more extended position, thereby exerting more shear force on their CCLs. The inclination of the patellar tendon is influenced by the position of the stifle but also by the relative relationship of relevant anatomic structures, such as the femoral condyles and proximal tibia. Two recent studies reported no difference in the dimensions, conformation or angulation of the distal femur between CCL deficient limbs and normal controls.21,61 However, these studies diverge in their conclusions regarding the conformation of the proximal aspect of the tibia in diseased compared with normal limbs. Guerrero et al61 reported the presence of an under-developed tibial tuberosity in 43 large breed dogs compared with

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38 normal dogs, whereas Mostafa et al21 measured similar widths of the proximal tibia in CCL deficient, contralateral, and normal limbs of Labrador Retrievers. The discrepancy between these studies could be breed related but is most likely attributed to differences in the methodology used to evaluate the conformation of the proximal tibia. Mostafa et al21 compared the entire width of the proximal aspect of the tibia normalized to the diameter of the distal tibia to palliate the confounding effects of size and magnification. Guerrero et al61 determined the size of the cranial aspect of the tibial tuberosity and expressed it relative to the radius of a circle outlining the articular surface of the tibia. These results were recently confirmed in a retrospective review of 219 radiographs normal, preoperative CCL deficient and post-TTA limbs.62 Although the overall width of the proximal tibia was identical between normal and CCL deficiency groups, the relative size of the tibial tuberosity was decreased in affected limbs, especially in dogs o 5 years of age.62 Taken together, these findings suggest that CCL deficiency may be associated with a relatively small cranial tuberosity in tibias that are of normal overall dimensions. The implications of this concept remain unclear in terms of prevention of CCLD. The cost and morbidity of TTA prohibit its application as a prophylactic procedure and no strategy has been proposed to stimulate the growth of the tibial tuberosity in immature dogs.

BIOMECHANICAL LOADING AND GAIT CHARACTERISTICS If traumatic rupture of the CCL has traditionally been attributed to sudden hyperextension and excessive internal rotation of a partially flexed stifle, the role of exercise in the pathogenesis of nontraumatic CCL deficiency has not been objectively evaluated and remains controversial. On one hand, disuse related to sedentary lifestyle or immobilization has been associated with nontraumatic CCL deficiency.63,64 The proposed mechanism involves not only a weakening of the ligament but also of other soft tissue stabilizers (muscles, ligaments and tendons) as they adjust to the lack of biomechanical loading.11,16 More recently, repetitive loading has been suggested to result in overuse and fatigue failure of the CCL deficiency.13,65,66 The cumulative effect of repetitive loading should correlate with the magnitude of the forces applied during each stance phase and could exacerbate a dynamic imbalance generated by other causative factors, such as conformation. This theory could account for the effects of obesity and could contribute to the incidence of CCL deficiency in large breed dogs, as higher loads would be placed on the knee in both instances. The biomechanical load placed on the CCL is influenced by the total force applied on the limb, but also by the activity of muscles acting on the knee (Fig 4). This concept has been well investigated in people, where joint kinetic, kinematic and electromyographic (EMG) studies have helped identify gait characteristics predisposing female athletes and explain their 3–8 times greater incidence of

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noncontact ACL injuries compared with male athletes engaged in jumping or pivoting sports.67–72 Gender differences in joint position, mobilization (amplitude and timing) and relative strength of quadriceps and hamstrings are believed to lead to anterior tibial loads overpowering active restraints to CTT during dynamic exercises.72 Coactivation of the hamstring and quadriceps muscles contribute to the overall stability of the knee, preventing cranial translation of the tibia as well as dynamic abduction of the knee.72 This synergistic action appears to be altered in female athletes, both in terms of magnitude as well as timing of muscle activation: a delayed and decreased mobilization of hamstrings in relation to the quadriceps group increase the load placed on the ACL.72–74 In dogs, the loss of the CCL as a passive constraint to CTT, results in cyclical patterns of cranial tibial subluxation and reduction during the stance and swing phases of gait, respectively.75,76 This observation suggests that the contraction of the quadriceps and gastrocnemius muscles, opposing ground reaction forces during weight bearing, prevail over the hamstring muscles: rendering them ineffective as a dynamic constraint to CTT. However, the contraction of the flexor muscles is strong enough during the swing phase to reduce the cranially displaced tibia. These observations support the concept of a dynamic imbalance between muscles acting on the stifle of dogs predisposed to CCLD similar to that described in people. Colborne et al57 consequently reported that adult Labrador Retrievers and Greyhounds displayed similar gait patterns, but Greyhounds generated flexor moments that were double those of Labradors, while the relative contribution of the stifle support mechanism was more than doubled in Labradors during the late stance phase. Greyhounds trotted faster than Labrador Retrievers in this study, but a later publication confirmed that velocity could not account for the difference in biomechanical characteristics between the 2 breeds.77 These results are encouraging as they support the concept of dynamic stifle instability predisposing Labradors to CCLD. However, they warrant further investigation because the morphometric data was extrapolated from a very small number of cadavers (4 Greyhounds and 3 Labradors) and could therefore not account for morphologic differences within breeds, especially Labradors. If these results are confirmed, the identification of biomechanical gait characteristics predisposing dogs to CCLD could serve as a basis for adopting a preventative strategy similar to that in humans, where neuromuscular training programs led to a relative risk reduction of 70% among participants.78,79

ARTHRITIS The presence of a lymphocytic–plasmacytic synovitis in CCL deficient knees is well established in dogs, and has been identified in about 67% of cases.80 The cellular and humoral immunopathological mechanisms involved in this condition have recently been reviewed.81 Briefly, B and T lymphocytes, activated (tartrate-resistant acid phospha-

Pathogenesis of Canine Cranial Cruciate Ligament Disease

tase-positive or TRAP1) macrophages, CD1c1 MHC class II1 dendritic cells and IgG1, IgM1 and IgA1 plasma cells infiltrate the synovium and diseased ligament.80,82,83 This type of cell population, along with the deposition of immunoglobulins and the expression of immune response genes are consistent with an antigen-specific immune process.80,82,84,85 Antigen stimulated dendritic cells (CD1c1 MHC class II1) are believed to present the antigen to naı¨ ve T lymphocytes. Activated CD41 T-lymphocytes can then engage macrophages, monocytes, B-lymphocytes, fibroblasts and synoviocytes into an inflammatory cascade leading to phagocytosis of debris, ligament degeneration and synovial proliferation. Most studies rely on comparisons between CCL deficiency and normal stifles. However, several investigators have also included a group of stifles affected by arthritis other than naturally occurring CCL deficiency (experimental transaction of the CCL for example) to differentiate changes associated with inflammation in general from those specific to CCL deficiency. Others have compared contralateral stifles of dogs with unilateral nontraumatic cruciate disease to try and establish the preclinical nature of the inflammatory process associated with CCL deficiency. Among these, de Bruin et al86,87 monitored cytokine mRNA expression and the presence of anticollagen type I antibodies in the synovial fluid of the diseased stifle, contralateral joint and left shoulder in 13 dogs with unilateral CCL deficiency over 12–18 months. Interpretation of this data is complicated by the presence of antibodies against collagen I in all 3 joints of most dogs, the small size of the population studied (6 of the 13 dogs developed contralateral CCL deficiency), cutoff values based on 2 shamoperated dogs, variability in pathology (complete versus partial CCL deficiency, meniscal disease) and titers within and between dogs. In spite of these limitations, antibody titers were higher in dogs with partial compared with complete tears of the CCL, which may reflect continued antigenic stimulation and release of collagen type I from damaged ligament into the articular space. Titers tended to increase in contralateral stifles that became CCL deficient during the study.86 Expression of IL-8 also tended to increase in these joints, further supporting the concept of an inflammatory process preceding the clinical stage of CCLD in dogs.87 However, CCL deficiency did not develop in all contralateral stifles with elevated anticollagen I antibodies titers, prompting the authors to conclude that the pathogenesis of CCLD could not be attributed to this mechanism alone. In fact, if collagen I released from a denatured ligament may initiate the lymphocytic–plasmacytic synovitis associated with CCLD, the cause of this ligament damage remains unknown. The initial insult to the ligament may result from repetitive and/or excessive biomechanical loading, the immune response exacerbating the degeneration of the CCL. Alternatively, sequestration of bacteria has recently been proposed as a causative factor for the inflammatory component of CCL deficiency. Translocation of circulating bacteria occurs commonly and has been incriminated in the pathogenesis of human arthritis,

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based on the isolation of DNA belonging to joint pathogens such as Borrelia burgdorferi and Chlamydia trachomatis in diseased joints.88,89 Bacterial DNA was isolated from synovial biopsies in 37% of 43 dogs with naturally occurring CCL deficiency, 7% of 16 stifles with experimental transection of the CCL and none of 12 normal dogs.88 DNA from environmental bacteria was only isolated from knees with naturally occurring CCL deficiency. The large body of evidence substantiating the presence of a preclinical immune-mediated synovitis in dogs with CCL deficiency warrants evaluation of immune-modifying therapies as a preventive strategy. The nature of the antigen causing this response remains unclear, limiting the ability to screen appropriate candidates from the general canine population. This strategy could however be first evaluated and subsequently implemented in dogs with unilateral CCL deficiency to prevent contralateral disease. This approach may also be relevant to the management of early CCLD, in stifles with joint effusion and minimum laxity.

CONCLUSIONS CCL deficiency in dogs is a multifactorial disease involving genetics, conformation factors, and an inflammatory component that together create an imbalance between the biomechanical forces placed on the ligament and its ability to sustain these loads, eventually leading to rupture and joint instability (Fig 1, Table 1). Numerous factors have been proposed as contributing to the pathogenesis of CCL deficiency, largely based on studies comparing canine limbs considered as diseased, normal, at low risk or predisposed to CCL deficiency. This approach faces multiple hurdles. The diseased group typically includes lame dogs with surgical confirmation of CCL deficiency. This group allows

identification of inflammatory processes occurring in diseased joints and can help determine skeletal factors predisposing dogs to CCL deficiency. However, the effects of lameness prevent the ability to investigate potential causative factors related to muscle conformation or gait characteristics. Defining a normal population has been even more challenging. Comparisons between breeds predisposed to CCL deficiency (Labrador Retrievers, Newfoundland) and those rarely affected by the condition (Greyhounds) do not clearly establish the relevance of interbreed differences for the pathogenesis of CCL deficiency. To palliate this limitation, older dogs of the same predisposed breed have been considered as normal controls. This alternative eliminates variations related to breed differences but introduces age as a variable between the diseased and normal populations. The presence of a factor in both predisposed and affected limbs, combined with its absence in normal controls provide the strongest evidence that this factor effectively contributes to the pathogenesis of CCL deficiency. Limbs considered at risk for CCL deficiency in clinical studies often consist of the sound contralateral stifle in dogs with nontraumatic unilateral cruciate disease. This assumption is based on epidemiologic studies of CCL deficiency, documenting contralateral disease in a third of patients within 8 months of the initial CCL deficiency.7,90,91 This study design eliminates interindividual variations between diseased and predisposed groups, and may help establish the preclinical existence of an inflammatory process or the contribution of skeletal conformation factors. However, differences in muscle conformation and/or gait analyses must be interpreted with caution as these may reflect both predisposition and compensation to CCL deficiency. Ultimately, the risk of developing CCL deficiency is unlikely to be determined based on consideration of a sole factor. Instead, this risk may eventually be calculated

Table 1 Factors Implicated in the Pathogenesis of Cranial Cruciate Ligament Disease, Proposed Mechanisms of Action and Related References in Small Animals Variable Genetics Genu varum Internal femoral torsion Medial patellar luxation Tibial torsion Intercondylar notch stenosis Cranial angulation of the proximal tibia, excessive TPA Early neutering Alignment of the patella tendon Sedentary lifestyle Body weight Dynamic muscle imbalance Lymphocytic–plasmacytic arthritis

Proposed Mechanisms Recessive mode of inheritance with 51% penetrance Excessive internal rotational forces Impingement of the CCL on a misaligned intercondylar notch Internal rotational forces Internal rotational forces Loss of restraint to CTT Internal rotational forces Impingement of the CCL on a narrow notch Increased cranial tibial thrust Excessive TPA and CTT Under-developed tibial tuberosity Cranial shear during contraction of the quadriceps muscle Weakening secondary to lack of biomechanical loading Fatigue failure Muscles contributing to CTT prevail over active restraints Immune mediated process triggered by: Denatured collagen I fibers Translocation of circulating bacteria

References Whitehair and colleagues12–15 Moore and colleagues11,21–23 Mostafa et al21 Moore and colleagues11,17,18,21 Moore and colleagues11,24 Souryal and colleagues28–36 Mostafa and colleagues21,39–44 Duerr and colleagues45–48 Mostafa and colleagues21,60–62 Moore and colleagues11,16,63,64 Duval and colleagues13,65,66 Colborne and colleagues57,75,76 Galloway and colleagues80–88

TPA, tibial plateau angle; CTT, cranial tibial thrust; CCl, cranial tibial thrust.

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with a mathematical model integrating several characteristics, the relative impact of each factor varying between individuals. To establish the validity of this model or the influence of a causative factor, large-scale prospective studies are needed to compare the long-term outcome of dogs considered as predisposed or at low risk for CCL deficiency. If the multifactorial nature of CCL deficiency complicates our ability to understand the pathogenesis of the disease, it increases the number of potential opportunities for prevention. This field of research is currently wide open and likely to expand in response to the awareness of the impact of CCL deficiency and the general trend toward preventive medicine in people and small animals. An objective evaluation of preventive strategies will consider their permanent effectiveness, affordability and a morbidity that should be inferior to that of the current standard for treatment. In parallel to these efforts, research should focus on developing a method for specific and sensitive detection of predisposed dogs, which is a prerequisite to large-scale application of any preventive program. Breeding based on genetic screening may provide a long-term mean of eradicating the disease in breeds with high OR for CCL deficiency. In the short term, modifications of phenotypic characteristics associated with CCL deficiency may be more realistic, while immune-modulating therapies may be relevant in dogs with unilateral or early evidence of cruciate disease.

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