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

 

 Buy Article Permissions and Reprints

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.

• 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.
  PubMedGoogle Scholar
• 2 Hayashi K, Frank JD, Dubinsky C. et al. Histological changes in ruptured canine cranial cruciate ligament. Vet Surg 2003; 32: 269-277.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  Article in Thieme ConnectPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 15 Spreng D, Sigrist N. et al. Stromelysin activity in canine cranial cruciate ligament rupture. Vet Comp Orthop Traumatol 1999; 12: 159-165.
  Article in Thieme ConnectPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 24 Blackburn Jr. WD. Validity of acute phase proteins as markers of disease activity. J Rheumatol Suppl 1994; 42: 9-13.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 29 Coughlan AR, Roberston DH, Bennett D. et al. Matrix metalloproteinases 2 and 9 in canine rheumatoid arthritis. Vet Rec 1998; 143: 219-223.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 34 Sanderson RO, Beata C, Flipo RM. et al. Systematic review of the management of canine osteoarthritis. Vet Rec 2009; 164: 418-424.
  CrossrefPubMedGoogle Scholar
• 35 Caspi D, Snel FW, Batt RM. et al. C-reactive protein in dogs. Am J Vet Res 1987; 48: 919-921.
  PubMedGoogle Scholar
• 36 Blackburn W. Validity of acute phase proteins as markers of disease activity. J Rheumatol 1994; 42: 9-13.
  PubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 43 Carter SD, Barnes A, Gilmore WH. Canine rheumatoid arthritis and inflammatory cytokines. Vet Immunol Immunopathol 1999; 69: 201-214.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar
• 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.
  PubMedGoogle Scholar
• 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.
  CrossrefPubMedGoogle Scholar