MMP-2 as an early synovial biomarker for cranial cruciate ligament disease in dogs

L. Boland; R. Danger; Q. Cabon; M. Rabillard; S. Brouard; B. Bouvy; O. Gauthier

doi:10.3415/VCOT-13-06-0082

Veterinary and Comparative Orthopaedics and Traumatology, Table of Contents

Vet Comp Orthop Traumatol 2014; 27(03): 210-215
DOI: 10.3415/VCOT-13-06-0082

Original Research

Schattauer GmbH

MMP-2 as an early synovial biomarker for cranial cruciate ligament disease in dogs

Authors

L. Boland

¹Frégis Veterinary Hospital, Arcueil, France
R. Danger

²INSERM U1064, Institut de Transplantation et de Recherche en Transplantation ITERT, Université de Nantes, France
Q. Cabon

³Department of Small Animal Surgery, ONIRIS Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering, La Chantrerie, Nantes Cedex 3, France
M. Rabillard

³Department of Small Animal Surgery, ONIRIS Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering, La Chantrerie, Nantes Cedex 3, France
S. Brouard

²INSERM U1064, Institut de Transplantation et de Recherche en Transplantation ITERT, Université de Nantes, France
B. Bouvy

¹Frégis Veterinary Hospital, Arcueil, France
O. Gauthier

³Department of Small Animal Surgery, ONIRIS Nantes-Atlantic College of Veterinary Medicine, Food Science and Engineering, La Chantrerie, Nantes Cedex 3, France

Abstract

Summary

Objectives: To measure the activity of matrix metalloproteinases (MMP)-2 and -9 in synovial fluid from the stifle joints of dogs with cranial cruciate ligament (CrCL) rupture and to compare that to values from contralateral stifle joints and dogs with clinically normal stifle joints. Additionally, the C-reactive protein (CRP) levels were also measured.

Methods: Fourteen large breed dogs with unilateral CrCL rupture and 11 large breed normal dogs were included in this prospective clinical study. Synovial fluid was collected from CrCL-ruptured stifle joints, contralateral clinically normal stifle joints of the same dogs, and stifle joints of normal dogs. Serum was also collected. Synovial fluid activities of MMP-2 and MMP-9 and serum CRP level were measured.

Results: The MMP-2 activity in synovial fluid was significantly higher in CrCL-ruptured joints compared to contralateral joints and to stifles from normal dogs. There was no significant difference in activity of MMP-2 in contralateral joints of CrCL-ruptured dogs compared to normal dogs. Both serum CRP level and MMP-9 activity did not differ significantly between the studied conditions.

Clinical significance: It was confirmed that MMP-2 activity is significantly related to CrCL rupture, but there was a failure to demonstrate any significant increase in the contralateral joints compared to the stifle joints of normal dogs. The MMP-2 involvement in progressing CrCL disease still has to be defined.

Keywords

Cranial cruciate ligament disease - contralateral rupture - matrix metalloproteinases - C-reactive protein - dog

Full Text

References

References
1 Vasseur PB, Berry CR. Progression of stifle osteoarthrosis following reconstruction of the cranial cruciate ligament in 21 dogs. J Am Anim Hosp Assoc 1992; 28: 129-136.
2 Hayashi K, Frank JD, Dubinsky C. et al. Histological changes in ruptured canine cranial cruciate ligament. Vet Surg 2003; 32: 269-277.
3 Doverspike M, Vasseur PB. et al. Contralateral cranial cruciate ligament rupture: incidence in 114 dogs. J Am Anim Hosp Assoc 1993; 29: 167-170.
4 Gardner DL, Bradley WA. et al. Synovitis after surgical division of the anterior cruciate ligament of the dog. Clin Exp Rheumatol 1984; 2: 11-15.
5 Lipowitz AJ, Wong PL, Stevens JB. Synovial membrane changes after experimental transection of the cranial cruciate ligament in dogs. Am J Vet Res 1985; 46: 1166-1170.
6 Bleedorn JA, Greuel E, Manley PA. et al. Synovitis in dogs with stable stifle joints and incipient cranial cruciate ligament rupture: a cross sectional study. Vet Surg 2011; 40: 531-543.
7 Myers SL, Brandt KD, O’Connor BL. et al. Synovitis and osteoarthritic changes in canine articular cartilage after anterior cruciate ligament transection. Effect of surgical hemostasis. Arthritis Rheum 1990; 33: 1406-1415.
8 Innes JF, Bacon D, Lynch C. et al. Long term outcome of surgery for dogs with cranial cruciate ligament deficiency. Vet Rec 2000; 147: 325-328.
9 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.
10 Johnson KA, Hay CW. et al. Cartilage-derived biomarkers of osteoarthritis in synovial fluid of dogs with naturally acquired rupture of the cranial cruciate ligament. Am J Vet Res 2002; 63: 775-781.
11 Innes JF, Sharif M, Barr AR. Changes in concentrations of biochemical markers of osteoarthritis following surgical repair of ruptured cranial cruciate ligaments in dogs. Am J Vet Res 1999; 60: 1164-1168.
12 Salinardi BJ, Roush JK. et al. Matrix metalloproteinase and tissue inhibitor of metalloproteinase in serum and synovial fluid of osteoarthritic dogs. Vet Comp Orthop Traumatol 2006; 19: 49-55.
13 Innes JF, Little CB, Hughes CE. et al. Products resulting from cleavage of the interglobular domain of aggrecan in samples of synovial fluid collected from dogs with early- and late stage osteoarthritis. Am J Vet Res 2005; 66: 1679-1685.
14 Muir P, Schamberger GM. 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.
15 Spreng D, Sigrist N. et al. Stromelysin activity in canine cranial cruciate ligament rupture. Vet Comp Orthop Traumatol 1999; 12: 159-165.
16 Muir P, Danova NA, Argyle DJ. et al. Collagenolytic protease expression in cranial cruciate ligament and synovial fluid in dogs with cranial cruciate ligament rupture. Vet Surg 2005; 34: 482-490.
17 Fosang AJ, Neame PJ, Last K. et al. The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. J Biol Chem 1992; 267: 19470-19474.
18 Clegg PD, Burke RM. et al. Characterisation of equine matrix metalloproteinases 2 and 9; and identification of the cellular sources of these enzymes in joints. Equine Vet J 1997; 29: 335-342.
19 Ceron JJ, Eckersall PD, Martynez-Subiela S. Acute phase proteins in dogs and cats: current knowledge and future perspectives. Vet Clin Pathol 2005; 34: 85-99.
20 Jergens AE, Schreiner CA. et al. A scoring index for disease activity in canine inflammatory bowel disease. J Vet Intern Med 2003; 17: 291-297.
21 Holm JL, Rozanski EA, Freeman LM. et al. C-reactive protein concentrations in canine acute pancreatitis. J Vet Emerg Crit Care 2004; 14: 183-186.
22 Onishi T, Inokuma H, Ohno K. et al. C-reactive protein concentrations in normal and diseased dogs-measured by laser nephelometric immunoassay. J Jpn Vet Med Assoc 2000; 53: 595-601.
23 Tecles F, Spiranelli E, Bonfanti U. et al. Preliminary studies of serum acute-phase protein concentrations in hematologic and neoplastic diseases of the dog. J Vet Intern Med 2005; 19: 865-870.
24 Blackburn Jr. WD. Validity of acute phase proteins as markers of disease activity. J Rheumatol Suppl 1994; 42: 9-13.
25 Rabillard M. et al. Matrix metalloproteinase activity in stifle synovial fluid of cranial cruciate ligament deficient dogs and effect of postoperative doxycycline treatment. Vet J 2012; 193: 271-273.
26 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.
27 Slocum B, Slocum TD. Tibial plateau leveling osteotomy for repair of cranial cruciate ligament rupture in the canine. Vet Clin North Small Anim Pract 1993; 23: 777-795.
28 D’Anjou M-A, Moreau M, Troncy E. et al. Osteophytosis, subchondral bone sclerosis, joint effusion and soft tissue thickening in canine experimental stifle osteoarthritis: comparison between 1.5T magnetic resonance imaging and computed radiography. Vet Surg 2008; 37: 166-177.
29 Coughlan AR, Roberston DH, Bennett D. et al. Matrix metalloproteinases 2 and 9 in canine rheumatoid arthritis. Vet Rec 1998; 143: 219-223.
30 Volk SW, Kapatkin AS, Haskins ME. et al. Gelatinase activity in synovial fluid and synovium obtained from healthy and osteoarthritic joints of dogs. Am J Vet Res 2003; 64: 1225-1233.
31 Elkins AD, Pechman R, Kearney MT. et al. A retrospective study evaluating the degree of degenerative joint disease in the stifle joints of dogs following surgical repair of anterior cruciate ligament. J Am Anim Hosp Assoc 1991; 27: 533-540.
32 Narama I, Masuoka-Nishiyama M, Matsuura T. et al. Morphogenesis of degenerative changes predisposing dogs to rupture of the cranial cruciate ligament. J Vet Med Sci 1996; 58: 1091-1097.
33 Girling SL, Bell SC, Whitelock RG. et al. Use of biochemical markers of osteoarthritis to investigate the potential disease modifying effect of tibial plateau levelling osteotomy. J Small Anim Pract 2006; 47: 708-714.
34 Sanderson RO, Beata C, Flipo RM. et al. Systematic review of the management of canine osteoarthritis. Vet Rec 2009; 164: 418-424.
35 Caspi D, Snel FW, Batt RM. et al. C-reactive protein in dogs. Am J Vet Res 1987; 48: 919-921.
36 Blackburn W. Validity of acute phase proteins as markers of disease activity. J Rheumatol 1994; 42: 9-13.
37 Borer LR, Peel JE, Seewald W. et al. Effect of carprofen, etodolac, meloxicam, or butorphanol in dogs with induced acute synovitis. Am J Vet Res 2003; 11: 1429-1437.
38 Fujiki M, Shineha J, Yamanokuchi K. et al. Effects of treatment with polysulfated glygosaminoglycan on serum cartilage oligomeric matrix protein and C-reactive protein concentrations, serum matrix metalloproteinase-2 and -9 activities, and lameness in dogs with osteoarthritis. Am J Vet Res 2007; 68: 827-833.
39 Hurter K. et al. Measurements of C-reactive protein in serum and lactate dehydrogenase in serum and synovial fluid of patients with osteoarthritis. Vet Journal 2005; 169: 281-285.
40 Hay CW, Chu Q, Budsberg SC. et al. Synovial fluid interleukin 6, tumor necrosis factor, and nitric oxide values in dogs with osteoarthritis secondary to cranial cruciate ligament rupture. Am J Vet Res 1997; 58: 1027-1035.
41 Venn G, Nietfeld JJ, Duits AJ. et al. Elevated synovial fluid levels of interleukin-6 and tumor necrosis factor associated with early experimental canine osteoarthritis. Arthritis Rheum 1993; 36: 819-826.
42 Schmidt-Rohlfing B, Thomsen M, Niedhart C. et al. Correlation of bone and cartilage markers in the synovial fluid with the degree of osteoarthritis. Rheumatol Int 2002; 21: 193-199.
43 Carter SD, Barnes A, Gilmore WH. Canine rheumatoid arthritis and inflammatory cytokines. Vet Immunol Immunopathol 1999; 69: 201-214.
44 Hegemann N, Wondimu A. et al. Synovial MMP- 3 and TIMP-1 levels and their correlation with cytokine expression in canine rheumatoid arthritis. Vet Immunol Immunopathol 2003; 91: 199-204.
45 Hegemann N, Kohn B, Brunnberg L. et al. Biomarkers of joint tissue metabolism in canine osteoarthritic and arthritic joint disorders. Osteoarthritis Cartilage 2002; 10: 714-721.
46 Breshears LA, Cook JL. et al. Detection and evaluation of matrix metalloproteinases involved in cruciate ligament disease in dogs using multiplex bead technology. Vet Surg 2010; 39: 306-314.
47 Wang Y, Tang Z, Xue R. et al. Combined effects of TNF-, IL-1, and HIF-1 on MMP-2 production in ACL fibroblasts under mechanical stretch: an in vitro study. J Orthop Resh 2011; 29: 1008-1014.
48 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 Path 2006; 134: 8-16.