Update on the aetiopathogenesis of canine cranial cruciate ligament disease

E. J. Comerford; K. Smith; K. Hayashi

doi:10.3415/VCOT-10-04-0055

Veterinary and Comparative Orthopaedics and Traumatology, Table of Contents

Vet Comp Orthop Traumatol 2011; 24(02): 91-98
DOI: 10.3415/VCOT-10-04-0055

Review Article

Schattauer GmbH

Update on the aetiopathogenesis of canine cranial cruciate ligament disease

Authors

E. J. Comerford

¹Department of Musculoskeletal Biology, Institute of Aging and Chronic Disease, University of Liverpool, Neston, UK

²School of Veterinary Clinical Science, University of Liverpool, Neston, UK
K. Smith

¹Department of Musculoskeletal Biology, Institute of Aging and Chronic Disease, University of Liverpool, Neston, UK
K. Hayashi

³JD Wheat Veterinary Orthopedic Research Laboratory, the Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA, USA.

Abstract

Summary

Cranial cruciate ligament disease (CCLD) is the most common cause of hindlimb lameness in the dog, being associated with and eventually leading to stifle osteoarthritis. Canine cranial cruciate ligament disease is a gradual degeneration of the ligament extra-cellular matrix (ECM) leading to ligament rupture. The aetiopathogenesis of this condition is still poorly understood but several risk factors have been identified such as breed, bodyweight, gender and conformation. Recent developments in this area include the role of genetics, stifle joint conformation, ligament ECM metabolism, and inflammation associated with immune-mediated disease within the stifle joint. A genetic mode of inheritance has been demonstrated in the Newfoundland which is predisposed to CCLD. Increased cellular metabolism within the cranial cruciate ligament has been directly associated with increased craniocaudal stifle joint laxity in dog breeds at high risk of CCLD. Conformation abnormalities, such as a narrowed distal femoral intercondylar notch, in high risk breeds have been shown to be associated with alterations in cranial cruciate ligament ultrastructure. Increased production of inflammatory cytokines, such as cathepsins and interleukins, by the stifle synovial cells may occur secondary to or may be an inciting cause of ligament degeneration. Future research endeavours will focus on the association between immune-mediated response and fibrocartilaginous metaplasia and matrix degradation within the cranial cruciate ligament, and whether this can be altered in all susceptible dogs or only certain breeds.

Keywords

Canine cranial cruciate ligament disease - epidemiology - genetics - metabolism

Full Text

References

References
1 Renstrom P, Ljungqvist A, Arendt E. et al. Non-contact ACL injuries in female athletes: an International Olympic Committee current concepts statement. Br J Sports Med 2008; 42: 394-412.
2 Bennett D, Tennant B, Lewis DG. et al. A reappraisal of anterior cruciate ligament disease in the dog. J Small Anim Pract 1988; 29: 275-297.
3 Duval JM, Budsberg SC, Flo GL. et al. Breed, sex, and body weight as risk factors for rupture of the cranial cruciate ligament in young dogs. J Am Vet Med Assoc 1999; 215: 811-814.
4 Whitehair JG, Vasseur PB, Willits NH. Epidemiology of cranial cruciate ligament rupture in dogs. J Am Vet Med Assoc 1993; 203: 1016-1019.
5 Witsberger TH, Villamil JA, Schultz LG. et al. Prevalence of and risk factors for hip dysplasia and cranial cruciate ligament deficiency in dogs. J Am Vet Med Assoc 2008; 232: 1818-1824.
6 Colborne GR, Innes JF, Comerford EJ. et al. Distribution of power across the hind limb joints in Labrador Retrievers and Greyhounds. Am J Vet Res 2005; 66: 1563-1571.
7 Brown DC, Conzemius MG, Shofer FS. Body weight as a predisposing factor for humeral condylar fractures, cranial cruciate rupture and intervertebral disc disease in Cocker Spaniels. Vet Comp Orthop Traumatol 1996; 9: 75-78.
8 Wilke VL, Zhang S, Evans RB. et al. Identification of chromosomal regions associated with cranial cruciate ligament rupture in a population of Newfoundlands. Am J Vet Res 2009; 70: 1013-1017.
9 Muir P, Fox R, Wu Q. et al. Seasonal variation in detection of bacterial DNA in arthritic stifle joints of dogs with cranial cruciate ligament rupture using PCR amplification of the 16S rRNA gene. Vet Microbiol 2010; 141: 127-133.
10 Comerford EJ, Tarlton JF, Wales A. et al. Ultrastructural differences in cranial cruciate ligaments from dogs of two breeds with a differing predisposition to ligament degeneration and rupture. J Comp Pathol 2006; 134: 8-16.
11 Vasseur PB, Pool RR, Arnoczky SP. et al. Correlative biomechanical and histologic study of the cranial cruciate ligament in dogs. Am J Veterinary Res 1985; 46: 1842-1854.
12 Whitehair JG, Vasseur PB, Willits NH. Epidemiology of cranial cruciate ligament rupture in dogs. J Am Vet Med Assoc 1993; 203: 1016-1020.
13 Buote N, Fusco J, Radasch R. Age, tibial plateau angle, sex, and weight as risk factors for contralateral rupture of the cranial cruciate ligament in Labradors. Vet Surg 2009; 38: 481-489.
14 Macias C, McKee WM, May C. Caudal proximal tibial deformity and cranial cruciate ligament rupture in small-breed dogs. J Small Anim Pract 2002; 43: 433-438.
15 Wilke VL, Conzemius MG, Kinghorn BP. et al. Inheritance of rupture of the cranial cruciate ligament in Newfoundlands. J Am Vet Med Assoc 2006; 228: 61-64.
16 Nielen AL, Knol BW, van Hagen MA. et al. [Genetic and epidemiological investigation of a birth cohort of boxers]. Tijdschr Diergeneeskd 2003; 128: 586-590.
17 Wilke VL, Conzemius MC, Rothschild MF. SNP detection and association analyses of candidate genes for rupture of the cranial cruciate ligament in the dog. Animal genetics 2005; 36: 519-521.
18 Temwichitr J, Hazewinkel HA, van Hagen MA. et al. Polymorphic microsatellite markers for genetic analysis of collagen genes in suspected collagenopathies in dogs. J Vet Med A Physiol Pathol Clin Med 2007; 54: 522-526.
19 Clements DN, Short AD, Barnes A. et al. A candidate gene study of canine joint diseases. J Hered 2010; 101: 54-60.
20 Harasen G. Canine cranial cruciate ligament rupture in profile:2002-2007. Can Vet J 2008; 49: 193-194.
21 Doverspike M, Vasseur PB, Harb MF. et al. Contra-lateral cranial cruciate ligament rupture: Incidence in 114 dogs. J Am Anim Hosp Assoc 1993; 29: 167-171.
22 Powers MY, Martinez SA, Lincoln JD. et al. Prevalence of cranial cruciate ligament rupture in a population of dogs with lameness previously attributed to hip dysplasia: 369 cases (1994–2003). J Am Vet Med Assoc 2005; 227: 1109-1111.
23 Slauterbeck JR, Pankratz K, Xu KT. et al. Canine ovariohysterectomy and orchiectomy increases the prevalence of ACL injury. Clin Orthop Relat Res 2004; 301-305.
24 Edney ATB, Smith PM. Study of obesity in dogs visiting veterinary practices in the United Kingdom. Vet Rec 1986; 118: 391-396.
25 Dannucci GA, Martin RB, Pattersonbuckendahl P. Ovariectomy and trabecular bone remodeling in the dog. Calcif Tissue Int 1987; 40: 194-199.
26 O'Hara A, Lim FL, Mazzatti DJ. et al. Microarray analysis identifies matrix metalloproteinases (MMPs) as key genes whose expression is up-regulated in human adipocytes by macrophage-conditioned medium. Pflugers Arch 2009; 458: 1103-1114.
27 Presle N, Pottie P, Dumond H. et al. Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production. Osteoarthritis Cartilage 2006; 14: 690-695.
28 Trayhurn P, Bing C, Wood IS. Adipose tissue and adipokines--energy regulation from the human perspective. J Nutr. 2006; 136: 1935S-1939S.
29 Eisele I, Wood IS, German AJ. et al. Adipokine gene expression in dog adipose tissues and dog white adipocytes differentiated in primary culture. Horm Metab Res 2005; 37: 474-481.
30 Wang JH. Mechanobiology of tendon. J Biomech 2006; 39: 1563-1582.
31 Hannafin JA, Attia EA, Henshaw R. et al. Effect of cyclic strain and plating matrix on cell proliferation and integrin expression by ligament fibroblasts. J Orthop Res 2006; 24: 149-158.
32 Henshaw DR, Attia E, Bhargava M. et al. Canine ACL fibroblast integrin expression and cell alignment in response to cyclic tensile strain in three-dimensional collagen gels. J Orthop Res 2006; 24: 481-490.
33 Jones GC, Corps AN, Pennington CJ. et al. Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon. Arthritis Rheum 2006; 54: 832-842.
34 Wang JH, Jia F, Yang G. et al. Cyclic mechanical stretching of human tendon fibroblasts increases the production of prostaglandin E2 and levels of cyclooxygenase expression: a novel in vitro model study. Connect Tissue Res 2003; 44: 128-133.
35 Egerbacher M, Arnoczky SP, Caballero O. et al. Loss of homeostatic tension induces apoptosis in tendon cells: an in vitro study. Clin Orthop Relat Res 2008; 466: 1562-1568.
36 Lavagnino M, Arnoczky SP, Egerbacher M. et al. Isolated fibrillar damage in tendons stimulates local collagenase mRNA expression and protein synthesis. J Biomech 2006; 39: 2355-2362.
37 Arnoczky SP, Lavagnino M, Egerbacher M. The mechanobiological aetiopathogenesis of tendinopathy: is it the over-stimulation or the under-stimulation of tendon cells?. Int J Exp Pathol 2007; 88: 217-226.
38 Newton PM, Mow VC, Gardner TR. et al. Winner of the 1996 Cabaud Award. The effect of lifelong exercise on canine articular cartilage. Am J Sports Med 1997; 25: 282-287.
39 Frank CB, Amiel D, Woo SL. et al. Normal ligament properties and ligament healing. Clin Orthop Relat Res 1985; 196: 15-27.
40 Narama I, Masuoka-Nishiyama M, Matsuura T. et al. Morphogenesis of degenerative changes predis-posing dogs to rupture of the cranial cruciate ligament. J Vet Med Sci 1996; 58: 1091-1097.
41 Paatsama S. Ligamentous injuries of the canine stifle joint. A clinical and experimental study. [Thesis]. Helsinki: Royal Veterinary College, Helsinki Finland; 1952
42 Hayashi K, Frank JD, Hao Z. et al. Evaluation of ligament fibroblast viability in ruptured cranial cruciate ligament of dogs. Am J Vet Res 2003; 64: 1010-1016.
43 Gyger O, Botteron C, Doherr M. et al. Detection and distribution of apoptotic cell death in normal and diseased canine cranial cruciate ligaments. Vet J 2007; 174: 371-377.
44 Krayer M, Rytz U, Oevermann A. et al. Apoptosis of ligamentous cells of the cranial cruciate ligament from stable stifle joints of dogs with partial cranial cruciate ligament rupture. Am J Vet Res 2008; 69: 625-630.
45 Hofer D, Forterre S, Schweighauser A. et al. Selective iNOS-inhibition does not influence apoptosis in ruptured canine cranial cruciate ligaments. Vet Comp Orthop Traumatol 2009; 22: 198-203.
46 Bruehlmann SB, Rattner JB, Matyas JR. et al. Regional variations in the cellular matrix of the annulus fibrosus of the intervertebral disc. J Anat 2002; 201: 159-171.
47 Lo IK, Ou Y, Rattner JP. et al. The cellular networks of normal ovine medial collateral and anterior cruciate ligaments are not accurately recapitulated in scar tissue. J Anat 2002; 200: 283-296.
48 Kobayashi S, Baba H, Uchida K. et al. Microvascular system of anterior cruciate ligament in dogs. J Orthop Res 2006; 24: 1509-1520.
49 Hayashi K, Frank JD, Dubinsky C. et al. Histologic changes in ruptured canine cranial cruciate ligament. Vet Surg 2003; 32: 269-277.
50 Muir P, Schamberger GM, Manley PA. et al. Localization of cathepsin K and tartrate-resistant acid phosphatase in synovium and cranial cruciate ligament in dogs with cruciate disease. Vet Surg 2005; 34: 239-246.
51 Comerford EJ, Innes JF, Tarlton JF. et al. Investigation of the composition, turnover, and thermal properties of ruptured cranial cruciate ligaments of dogs. Am J Vet Res 2004; 65: 1136-1141.
52 Comerford EJ, Tarlton JF, Innes JF. et al. Metabolism and composition of the canine anterior cruciate ligament relate to differences in knee joint mechanics and predisposition to ligament rupture. J Orthop Res 2005; 23: 61-66.
53 Waggett AD, Kwan APL, Woodnutt DJ. et al. Collagens in fibrocartilages at the Achilles tendon insertion -a biochemical, molecular biological and immunohistochemical study. Proceedings of the Orthopaedic Research Society 1996; 21: 25.
54 Stouffer DC, Butler DL, Kim H. Tension-torsion characteristics of the canine anterior cruciate ligament - Part I: Theoretical framework. J Biomech Eng 1983; 105: 154-159.
55 Alm A, Ekstrom H, Stromberg B. Tensile strength of the anterior cruciate ligament in the dog. Acta chirurgica Scandinavica. 1974; 445: 15-23.
56 Wingfield C, Amis AA, Stead AC. et al. Cranial cruciate stability in the rottweiler and racing greyhound: an in vitro study. J Small Anim Pract 2000; 41: 193-197.
57 Wingfield C, Amis AA, Stead AC. et al. Comparison of the biomechanical properties of rottweiler and racing greyhound cranial cruciate ligaments. J Small Anim Pract 2000; 41: 303-307.
58 Salo P. The role of joint innervation in the pathogenesis of arthritis. Canadian journal of surgery. 1999; 42: 91-100.
59 Ivie TJ, Bray RC, Salo PT. Denervation impairs healing of the rabbit medial collateral ligament. J Orthop Res 2002; 20: 990-995.
60 Beye JA, Hart DA, Bray RC. et al. Denervation alters mRNA levels of repair-associated genes in a rabbit medial collateral ligament injury model. J Orthop Res 2006; 24: 1842-1853.
61 Alentorn-Geli E, Myer GD, Silvers HJ. et al. Prevention of non-contact anterior cruciate ligament injuries in soccer players. Part 2: a review of prevention programs aimed to modify risk factors and to reduce injury rates. Knee Surg Sports Traumatol Arthrosc. 2009; 17: 859-879.
62 Comerford EJ, Tarlton JF, Avery NC. et al. Distal fe-moral intercondylar notch dimensions and their relationship to composition and metabolism of the canine anterior cruciate ligament. Osteoarthritis Cartilage 2006; 14: 273-278.
63 Read RA, Robins GM. Deformity of the proximal tibia in dogs. Vet Rec 1982; 111: 295-298.
64 Duerr FM, Duncan CG, Savicky RS. et al. Risk factors for excessive tibial plateau angle in large-breed dogs with cranial cruciate ligament disease. J Am Vet Med Assoc 2007; 231: 1688-1691.
65 Ragetly CA, Griffon DJ, Thomas JE. et al. Noninvasive determination of body segment parameters of the hind limb in Labrador Retrievers with and without cranial cruciate ligament disease. Am J Vet Res 2008; 69: 1188-1196.
66 Mostafa AA, Griffon DJ, Thomas MW. et al. Morphometric characteristics of the pelvic limbs of Labrador Retrievers with and without cranial cruciate ligament deficiency. Am J Vet Res 2009; 70: 498-507.
67 Guastella DB, Fox DB, Cook JL. Tibial plateau angle in four common canine breeds with cranial cruciate ligament rupture, and its relationship to meniscal tears. Vet Comp Orthop Traumatol 2008; 21: 125-128.
68 Selmi AL, Padilha Filho JG. Rupture of the cranial cruciate ligament associated with deformity of the proximal tibia in five dogs. J Small Anim Pract 2001; 42: 390-393.
69 Reif U, Probst CW. Comparison of tibial plateau angles in normal and cranial cruciate deficient stifles of Labrador retrievers. Vet Surg 2003; 32: 385-389.
70 Wilke VL, Conzemius MG, Besancon MF. et al. Comparison of tibial plateau angle between clinically normal Greyhounds and Labrador Retrievers with and without rupture of the cranial cruciate ligament. J Am Vet Med Assoc 2002; 221: 1426-1429.
71 Aiken SW, Kass PH, Toombs JP. Intercondylar notch width in dogs with and without cranial cruciate ligament injuries. Vet Comp Orthop Traumatol 1995; 8: 128-132.
72 Quasnichka HL, Anderson-MacKenzie JM, Tarlton JF. et al. Cruciate ligament laxity and femoral inter-condylar notch narrowing in early-stage knee osteoarthritis. Arthritis Rheum 2005; 52: 3100-3109.
73 Stein V, Li L, Guermazi A. et al. The relation of fe-moral notch stenosis to ACL tears in persons with knee osteoarthritis. Osteoarthritis Cartilage 2010; 18: 192-199.
74 Guerrero TG, Geyer H, Hassig M. et al. Effect of conformation of the distal portion of the femur and proximal portion of the tibia on the pathogenesis of cranial cruciate ligament disease in dogs. Am J Vet Res 2007; 68: 1332-1337.
75 Inauen R, Koch D, Bass M. et al. Tibial tuberosity conformation as a risk factor for cranial cruciate ligament rupture in the dog. Vet Comp Orthop Traumatol 2009; 22: 16-20.
76 Radin EL, Rose RM. Role of subchondral bone in the initation and progression of cartilage damage. Clin Orth 1986; 213: 34-40.
77 Bailey AJ, Mansell JP. Do Subchondral Bone Changes Exacerbate or Precede Articular Cartilage Destruction in Osteoarthritis of the Elderly?. Ger-ontology 1997; 43: 296-304.
78 Quasnichka HL, Anderson-MacKenzie JM, Bailey AJ. Subchondral bone and ligament changes precede cartilage degradation in guinea pig osteoarthritis. Biorheology 2006; 43: 389-397.
79 D'Anjou MA, Moreau M, Troncy E. et al. Osteophytosis, subchondral bone sclerosis, joint effusion and soft tissue thickening in canine experimental stifle osteoarthritis: comparison between 1.5 T magnetic resonance imaging and computed radiography. Vet Surg. 2008; 37: 166-177.
80 Winegardner KR, Scrivani PV, Krotscheck U. et al. Magnetic resonance imaging of subarticular bone marrow lesions in dogs with stifle lameness. Vet Radiol Ultrasound. 2007; 48: 312-317.
81 Doom M, de Bruin T, de Rooster H. et al. Immuno-pathological mechanisms in dogs with rupture of the cranial cruciate ligament. Vet Immunol Immunopathol 2008; 125: 143-161.
82 Muir P, Schaefer SL, Manley PA. et al. Expression of immune response genes in the stifle joint of dogs with oligoarthritis and degenerative cranial cruciate ligament rupture. Vet Immunol Immunopathol 2007; 119: 214-221.
83 Niebauer GW, Wolf B, Bashey RI. et al. Antibodies to Canine Collagen Types I and II in Dogs with Spontaneous Cruciate Ligament Rupture and Osetoarthritis. Arthritis Rheum 1987; 30: 319-328.
84 Lawrence D, Bao SS, Canfield PJ. et al. Elevation of immunoglobulin deposition in the synovial membrane of dogs with cranial cruciate ligament rupture. Vet Immunol Immunopathol 1998; 65: 89-96.
85 de Bruin T, de Rooster H, van Bree H. et al. Interleukin-8 mRNA expression in synovial fluid of canine stifle joints with osteoarthritis. Vet Immunol Immunopathol 2005; 108: 387-397.
86 de Bruin T, de Rooster H, van Bree H. et al. Evaluation of anticollagen type I antibody titers in synovial fluid of both stifle joints and the left shoulder joint of dogs with unilateral cranial cruciate disease. Am J Vet Res 2007; 68: 283-289.
87 de Bruin T, de Rooster H, van Bree H. et al. Cytokine mRNA expression in synovial fluid of affected and contralateral stifle joints and the left shoulder joint in dogs with unilateral disease of the stifle joint. Am J Vet Res 2007; 68: 953-961.
88 Muir P, Hayashi K, Manley PA. et al. Evaluation of tartrate-resistant acid phosphatase and cathepsin K in ruptured cranial cruciate ligaments in dogs. Am J Vet Res 2002; 63: 1279-1284.
89 Muir P, Danova NA, Argyle DJ. et al. Collagenolytic protease expression in cranial cruciate ligament and stifle synovial fluid in dogs with cranial cruciate ligament rupture. Vet Surg 2005; 34: 482-490.
90 Tang ZY, Yang L, Wang YQ. et al. Contributions of Different Intraarticular Tissues to the Acute Phase Elevation of Synovial Fluid MMP-2 following Rat ACL Rupture. J Orthop Res 2009; 27: 243-248.
91 Muir P, Oldenhoff WE, Hudson AP. et al. Detection of DNA from a range of bacterial species in the knee joints of dogs with inflammatory knee arthritis and associated degenerative anterior cruciate ligament rupture. Microb Pathog 2007; 42: 47-55.
92 Arnoczky SP, Rubin RM, Marshall JL. Microvasculature of the cruciate ligaments and its response to injury. An experimental study in dogs. J Bone Joint Surg Am 1979; 61: 1221-1229.
93 Murray MM, Spindler KP, Ballard P. et al. Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen-platelet-rich plasma scaffold. J Orthop Res. 2007; 25: 1007-1017.
94 Spindler KP, Murray MM, Devin C. et al. The central ACL defect as a model for failure of intra-articular healing. J Orthop Res 2006; 24: 401-406.
95 Rosc D, Powierza W, Zastawna E. et al. Post-traumatic plasminogenesis in intraarticular exudate in the knee joint. Med Sci Monit 2002; 8: CR371-CR378.
96 Murray MM. Current status and potential of primary ACL repair. Clin Sports Med 2009; 28: 51-61.
97 Spreng D, Sigrist N, Jungi T. et al. Nitric oxide meta-bolite production in the cranial cruciate ligament, synovial membrane, and articular cartilage of dogs with cranial cruciate ligament rupture. Am J Vet Res 2000; 61: 530-536.
98 Jauernig S, Schweighauser A, Reist M. et al. The effects of doxycycline on nitric oxide and stromelysin production in dogs with cranial cruciate ligament rupture. Vet Surg 2001; 30: 132-139.
99 Cao M, Stefanovic-Racic M, Georgescu HI. et al. Does nitric oxide help explain the differential healing capacity of the anterior cruciate, posterior cruciate, and medial collateral ligaments?. Am J Sports Med 2000; 28: 176-182.
100 Louis E, Remer KA, Doherr MG. et al. Nitric oxide and metalloproteinases in canine articular ligaments: a comparison between the cranial cruciate, the medial genual collateral and the femoral head ligament. Vet J 2006; 172: 466-472.
101 Nagineni CN, Amiel D, Green MH. et al. Characterization of the intrinsic properties of the anterior cruciate and medial collateral ligament cells: an in vitro cell culture study. J Orthop Res 1992; 10: 465-475.
102 Geiger MH, Green MH, Monosov A. et al. An in vitro assay of anterior cruciate ligament (ACL) and medial collateral ligament (MCL) cell migration. Connect Tissue Res 1994; 30: 215-224.
103 Amiel D, Chu CR, Lee J. Effect of loading on metabolism and repair of tendons and ligaments. In: Gordon SL, Blair SJ, Fine LJ. editors Repetitive motion disorders of the upper extremity Rosemount (IL, USA): American Academy of Orthopedic Surgeons; 1995: 217-230.
104 Spindler KP, Andrish JT, Miller RR. et al. Distribution of cellular repopulation and collagen synthesis in a canine anterior cruciate ligament auto-graft. J Orthop Res 1996; 14: 384-389.
105 Tirgari M, Vaughan LC. Arthritis of the canine stifle joint. Vet Rec 1975; 96: 394-399.
106 O'Donoghue DH, Frank GR, Jeter GL. et al. Repair and reconstruction of the anterior cruciate ligament in dogs. Factors influencing long-term results. J Bone Joint Surg Am 1971; 53: 710-718.
107 Cook JL. Cranial cruciate ligament disease in dogs: biology versus biomechanics. Vet Surg 2010; 39: 270-277.