Download PDF
J Knee Surg 2011; 24(4): 251-264
DOI: 10.1055/s-0031-1297361
SPECIAL FOCUS SECTION

© Thieme Medical Publishers

Using Animal Models in Osteoarthritis Biomarker Research

Bridget C. Garner1 , Aaron M. Stoker2 , Keiichi Kuroki2 , Richard Evans3 , Cristi Reeves Cook2 , James L. Cook2
  • 1Department of Veterinary Pathology, University of Georgia, Athens, Georgia
  • 2Comparative Orthopaedic Laboratory, University of Missouri, Columbia, Missouri
  • 3Waukesha, Wisconsin
Further Information

Publication History

Publication Date:
01 December 2011 (online)

    Permissions and Reprints

ABSTRACT

Osteoarthritis (OA) is a disease that commonly affects human and veterinary patients. Animal models are routinely used for OA research, and the dog is a nearly ideal species for translational investigation of human OA biomarkers. The cytokine, chemokine, and matrix metalloprotease (MMP) profiles of synovial fluid, serum, and urine from dogs with surgically induced and naturally occurring OA were compared with dogs without OA using xMAP technology (Qiagen Inc., Valencia, CA). Markers that exhibited significant differences between groups were identified (monocyte chemoattractant protein 1 [MCP1], interleukin 8 [IL8], keratinocyte-derived chemoattractant [KC], and MMP2 and MMP3), and their sensitivities and specificities were calculated to determine their diagnostic usefulness in a future biomarker panel. Synovial fluid IL8 was the most sensitive, but MCP1 was also highly sensitive and specific. The alterations in KC suggested that it may differentiate between cruciate disease and other types of OA, and the MMPs were most sensitive and specific in the serum. This study provided additional insight to the participation of cytokines, chemokines, and MMPs in OA, and potential diagnostic biomarker candidates were identified. A brief literature review of other biomarker candidates previously examined using animal models is discussed.

KEYWORDS

Osteoarthritis - biomarker - chemokine - matrix metalloprotease

REFERENCES

  • 1 Helmick C G, Felson D T, Lawrence R C National Arthritis Data Workgroup et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I.  Arthritis Rheum. 2008;  58 (1) 15-25
    Google Scholar
  • 2 Ray A, Kuroki K, Cook J L et al.. Induction of matrix metalloproteinase 1 gene expression is regulated by inflammation-responsive transcription factor SAF-1 in osteoarthritis.  Arthritis Rheum. 2003;  48 (1) 134-145
    Google Scholar
  • 3 Kuroki K, Stoker A M, Cook J L. Effects of proinflammatory cytokines on canine articular chondrocytes in a three-dimensional culture.  Am J Vet Res. 2005;  66 (7) 1187-1196
    Google Scholar
  • 4 Goldring M B. The role of cytokines as inflammatory mediators in osteoarthritis: lessons from animal models.  Connect Tissue Res. 1999;  40 (1) 1-11
    Google Scholar
  • 5 Scanzello C R, Plaas A, Crow M K. Innate immune system activation in osteoarthritis: is osteoarthritis a chronic wound?.  Curr Opin Rheumatol. 2008;  20 (5) 565-572
    Google Scholar
  • 6 Borzi R M, Mazzetti I, Macor S et al.. Flow cytometric analysis of intracellular chemokines in chondrocytes in vivo: constitutive expression and enhancement in osteoarthritis and rheumatoid arthritis.  FEBS Lett. 1999;  455 (3) 238-242
    Google Scholar
  • 7 Borzì R M, Mazzetti I, Cattini L, Uguccioni M, Baggiolini M, Facchini A. Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines.  Arthritis Rheum. 2000;  43 (8) 1734-1741
    Google Scholar
  • 8 Fernandes J C, Martel-Pelletier J, Pelletier J P. The role of cytokines in osteoarthritis pathophysiology.  Biorheology. 2002;  39 (1-2) 237-246
    Google Scholar
  • 9 Hegemann N, Wondimu A, Kohn B, Brunnberg L, Schmidt M F. Cytokine profile in canine immune-mediated polyarthritis and osteoarthritis.  Vet Comp Orthop Traumatol. 2005;  18 (2) 67-72
    Google Scholar
  • 10 Hulejová H, Baresová V, Klézl Z, Polanská M, Adam M, Senolt L. Increased level of cytokines and matrix metalloproteinases in osteoarthritic subchondral bone.  Cytokine. 2007;  38 (3) 151-156
    Google Scholar
  • 11 Klatt A R, Paul-Klausch B, Klinger G et al.. A critical role for collagen II in cartilage matrix degradation: collagen II induces pro-inflammatory cytokines and MMPs in primary human chondrocytes.  J Orthop Res. 2009;  27 (1) 65-70
    Google Scholar
  • 12 Sandell L J, Xing X, Franz C, Davies S, Chang L W, Patra D. Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1beta.  Osteoarthritis Cartilage. 2008;  16 (12) 1560-1571
    Google Scholar
  • 13 Tetlow L C, Adlam D J, Woolley D E. Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes.  Arthritis Rheum. 2001;  44 (3) 585-594
    Google Scholar
  • 14 Borden P, Solymar D, Sucharczuk A, Lindman B, Cannon P, Heller R A. Cytokine control of interstitial collagenase and collagenase-3 gene expression in human chondrocytes.  J Biol Chem. 1996;  271 (38) 23577-23581
    Google Scholar
  • 15 Schröder J M, Persoon N L, Christophers E. Lipopolysaccharide-stimulated human monocytes secrete, apart from neutrophil-activating peptide 1/interleukin 8, a second neutrophil-activating protein. NH2-terminal amino acid sequence identity with melanoma growth stimulatory activity.  J Exp Med. 1990;  171 (4) 1091-1100
    Google Scholar
  • 16 Venn G, Nietfeld J J, Duits A J et al.. Elevated synovial fluid levels of interleukin-6 and tumor necrosis factor associated with early experimental canine osteoarthritis.  Arthritis Rheum. 1993;  36 (6) 819-826
    Google Scholar
  • 17 Villiger P M, Terkeltaub R, Lotz M. Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes.  J Immunol. 1992;  149 (2) 722-727
    Google Scholar
  • 18 Tiku K, Thakker-Varia S, Ramachandrula A, Tiku M L. Articular chondrocytes secrete IL-1, express membrane IL-1, and have IL-1 inhibitory activity.  Cell Immunol. 1992;  140 (1) 1-20
    Google Scholar
  • 19 Aigner T, Cook J L, Gerwin N et al.. Histopathology atlas of animal model systems - overview of guiding principles.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S2-S6
    Google Scholar
  • 20 Cook J L, Kuroki K, Visco D, Pelletier J P, Schulz L, Lafeber F P. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the dog.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S66-S79
    Google Scholar
  • 21 Gerwin N, Bendele A M, Glasson S, Carlson C S. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S24-S34
    Google Scholar
  • 22 Kraus V B, Huebner J L, DeGroot J, Bendele A. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the guinea pig.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S35-S52
    Google Scholar
  • 23 Laverty S, Girard C A, Williams J M, Hunziker E B, Pritzker K P. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rabbit.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S53-S65
    Google Scholar
  • 24 McIlwraith C W, Frisbie D D, Kawcak C E, Fuller C J, Hurtig M, Cruz A. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the horse.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S93-S105
    Google Scholar
  • 25 Poole R, Blake S, Buschmann M et al.. Recommendations for the use of preclinical models in the study and treatment of osteoarthritis.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S10-S16
    Google Scholar
  • 26 Glasson S S, Chambers M G, Van Den Berg W B, Little C B. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S17-S23
    Google Scholar
  • 27 Little C B, Smith M M, Cake M A, Read R A, Murphy M J, Barry F P. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in sheep and goats.  Osteoarthritis Cartilage. 2010;  18 (Suppl 3) S80-S92
    Google Scholar
  • 28 Johnston S A. Osteoarthritis. Joint anatomy, physiology, and pathobiology.  Vet Clin North Am Small Anim Pract. 1997;  27 (4) 699-723
    Google Scholar
  • 29 Pond M J, Nuki G. Experimentally-induced osteoarthritis in the dog.  Ann Rheum Dis. 1973;  32 (4) 387-388
    Google Scholar
  • 30 Luther J K, Cook C R, Cook J L. Meniscal release in cruciate ligament intact stifles causes lameness and medial compartment cartilage pathology in dogs 12 weeks postoperatively.  Vet Surg. 2009;  38 (4) 520-529
    Google Scholar
  • 31 Bendele A M, Hulman J F. Spontaneous cartilage degeneration in guinea pigs.  Arthritis Rheum. 1988;  31 (4) 561-565
    Google Scholar
  • 32 Frisbie D D, Al-Sobayil F, Billinghurst R C, Kawcak C E, McIlwraith C W. Changes in synovial fluid and serum biomarkers with exercise and early osteoarthritis in horses.  Osteoarthritis Cartilage. 2008;  16 (10) 1196-1204
    Google Scholar
  • 33 Frisbie D D, Kawcak C E, McIlwraith C W. Evaluation of the effect of extracorporeal shock wave treatment on experimentally induced osteoarthritis in middle carpal joints of horses.  Am J Vet Res. 2009;  70 (4) 449-454
    Google Scholar
  • 34 Frisbie D D, Kawcak C E, Trotter G W, Powers B E, Walton R M, McIlwraith C W. Effects of triamcinolone acetonide on an in vivo equine osteochondral fragment exercise model.  Equine Vet J. 1997;  29 (5) 349-359
    Google Scholar
  • 35 Janusz M J, Bendele A M, Brown K K, Taiwo Y O, Hsieh L, Heitmeyer S A. Induction of osteoarthritis in the rat by surgical tear of the meniscus: Inhibition of joint damage by a matrix metalloproteinase inhibitor.  Osteoarthritis Cartilage. 2002;  10 (10) 785-791
    Google Scholar
  • 36 Moore E E, Bendele A M, Thompson D L et al.. Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis.  Osteoarthritis Cartilage. 2005;  13 (7) 623-631
    Google Scholar
  • 37 De Gruttola V G, Clax P, DeMets D L et al.. Considerations in the evaluation of surrogate endpoints in clinical trials: Summary of a National Institutes of Health workshop.  Control Clin Trials. 2001;  22 (5) 485-502
    Google Scholar
  • 38 Bauer D C, Hunter D J, Abramson S B Osteoarthritis Biomarkers Network et al. Classification of osteoarthritis biomarkers: a proposed approach.  Osteoarthritis Cartilage. 2006;  14 (8) 723-727
    Google Scholar
  • 39 Kraus V B. Osteoarthritis year 2010 in review: biochemical markers.  Osteoarthritis Cartilage. 2011;  19 (4) 346-353
    Google Scholar
  • 40 McIlwraith C W. Use of synovial fluid and serum biomarkers in equine bone and joint disease: a review.  Equine Vet J. 2005;  37 (5) 473-482
    Google Scholar
  • 41 Thonar E J. Molecular markers of metabolic changes in osteoarthritis.  Osteoarthritis Cartilage. 1999;  7 (3) 338-339
    Google Scholar
  • 42 Matyas J R, Atley L, Ionescu M, Eyre D R, Poole A R. Analysis of cartilage biomarkers in the early phases of canine experimental osteoarthritis.  Arthritis Rheum. 2004;  50 (2) 543-552
    Google Scholar
  • 43 Cawston T, Billington C, Cleaver C et al.. The regulation of MMPs and TIMPs in cartilage turnover.  Ann N Y Acad Sci. 1999;  878 120-129
    Google Scholar
  • 44 Bonassar L J, Frank E H, Murray J C et al.. Changes in cartilage composition and physical properties due to stromelysin degradation.  Arthritis Rheum. 1995;  38 (2) 173-183
    Google Scholar
  • 45 Lohmander L S, Saxne T, Heinegård D K. Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis.  Ann Rheum Dis. 1994;  53 (1) 8-13
    Google Scholar
  • 46 Misumi K, Vilim V, Carter S D, Ichihashi K, Oka T, Sakamoto H. Concentrations of cartilage oligomeric matrix protein in dogs with naturally developing and experimentally induced arthropathy.  Am J Vet Res. 2002;  63 (4) 598-603
    Google Scholar
  • 47 Barksby H E, Milner J M, Patterson A M et al.. Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: implications for cartilage degradation in arthritis.  Arthritis Rheum. 2006;  54 (10) 3244-3253
    Google Scholar
  • 48 Billinghurst R C, Dahlberg L, Ionescu M et al.. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage.  J Clin Invest. 1997;  99 (7) 1534-1545
    Google Scholar
  • 49 Huebner J L, Otterness I G, Freund E M, Caterson B, Kraus V B. Collagenase 1 and collagenase 3 expression in a guinea pig model of osteoarthritis.  Arthritis Rheum. 1998;  41 (5) 877-890
    Google Scholar
  • 50 Shlopov B V, Lie W R, Mainardi C L, Cole A A, Chubinskaya S, Hasty K A. Osteoarthritic lesions: involvement of three different collagenases.  Arthritis Rheum. 1997;  40 (11) 2065-2074
    Google Scholar
  • 51 Conrozier T, Poole A R, Ferrand F et al.. Serum concentrations of type II collagen biomarkers (C2C, C1, 2C and CPII) suggest different pathophysiologies in patients with hip osteoarthritis.  Clin Exp Rheumatol. 2008;  26 (3) 430-435
    Google Scholar
  • 52 Arican M, Carter S D, Bennett D, May C. Measurement of glycosaminoglycans and keratan sulphate in canine arthropathies.  Res Vet Sci. 1994;  56 (3) 290-297
    Google Scholar
  • 53 Campion G V, McCrae F, Schnitzer T J, Lenz M E, Dieppe P A, Thonar E J. Levels of keratan sulfate in the serum and synovial fluid of patients with osteoarthritis of the knee.  Arthritis Rheum. 1991;  34 (10) 1254-1259
    Google Scholar
  • 54 Sondergaard B C, Schultz N, Madsen S H, Bay-Jensen A C, Kassem M, Karsdal M A. MAPKs are essential upstream signaling pathways in proteolytic cartilage degradation: divergence in pathways leading to aggrecanase and MMP-mediated articular cartilage degradation.  Osteoarthritis Cartilage. 2010;  18 (3) 279-288
    Google Scholar
  • 55 Poole A R, Ionescu M, Swan A, Dieppe P A. Changes in cartilage metabolism in arthritis are reflected by altered serum and synovial fluid levels of the cartilage proteoglycan aggrecan. Implications for pathogenesis.  J Clin Invest. 1994;  94 (1) 25-33
    Google Scholar
  • 56 Chaganti R K, Kelman A, Lui L Study Of Osteoporotic Fractures Research Group (SOF) et al. Change in serum measurements of cartilage oligomeric matrix protein and association with the development and worsening of radiographic hip osteoarthritis.  Osteoarthritis Cartilage. 2008;  16 (5) 566-571
    Google Scholar
  • 57 Hunter D J, Li J, LaValley M et al.. Cartilage markers and their association with cartilage loss on magnetic resonance imaging in knee osteoarthritis: the Boston Osteoarthritis Knee Study.  Arthritis Res Ther. 2007;  9 (5) R108
    Google Scholar
  • 58 Bruyere O, Collette J, Kothari M et al.. Osteoarthritis, magnetic resonance imaging, and biochemical markers: a one year prospective study.  Ann Rheum Dis. 2006;  65 (8) 1050-1054
    Google Scholar
  • 59 King K B, Lindsey C T, Dunn T C, Ries M D, Steinbach L S, Majumdar S. A study of the relationship between molecular biomarkers of joint degeneration and the magnetic resonance-measured characteristics of cartilage in 16 symptomatic knees.  Magn Reson Imaging. 2004;  22 (8) 1117-1123
    Google Scholar
  • 60 Qi C, Changlin H. Levels of biomarkers correlate with magnetic resonance imaging progression of knee cartilage degeneration: a study on canine.  Knee Surg Sports Traumatol Arthrosc. 2007;  15 (7) 869-878
    Google Scholar
  • 61 Schmidt-Rohlfing B, Thomsen M, Niedhart C, Wirtz D C, Schneider U. Correlation of bone and cartilage markers in the synovial fluid with the degree of osteoarthritis.  Rheumatol Int. 2002;  21 (5) 193-199
    Google Scholar
  • 62 Wong P K, Young L, Vaile J H et al.. Telopeptides as markers of bone turnover in rheumatoid arthritis and osteoarthritis.  Intern Med J. 2004;  34 (9-10) 539-544
    Google Scholar
  • 63 Bruyere O, Collette J H, Ethgen O et al.. Biochemical markers of bone and cartilage remodeling in prediction of longterm progression of knee osteoarthritis.  J Rheumatol. 2003;  30 (5) 1043-1050
    Google Scholar
  • 64 Arican M, Carter S D, Bennett D. Osteocalcin in canine joint diseases.  Br Vet J. 1996;  152 (4) 411-423
    Google Scholar
  • 65 Billinghurst R C, Buxton E M, Edwards M G, McGraw M S, McIlwraith C W. Use of an antineoepitope antibody for identification of type-II collagen degradation in equine articular cartilage.  Am J Vet Res. 2001;  62 (7) 1031-1039
    Google Scholar
  • 66 van Meurs J, van Lent P, Stoop R et al.. Cleavage of aggrecan at the Asn341-Phe342 site coincides with the initiation of collagen damage in murine antigen-induced arthritis: a pivotal role for stromelysin 1 in matrix metalloproteinase activity.  Arthritis Rheum. 1999;  42 (10) 2074-2084
    Google Scholar
  • 67 Freemont A J, Hampson V, Tilman R, Goupille P, Taiwo Y, Hoyland J A. Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific.  Ann Rheum Dis. 1997;  56 (9) 542-549
    Google Scholar
  • 68 Karran E H, Young T J, Markwell R E, Harper G P. In vivo model of cartilage degradation—effects of a matrix metalloproteinase inhibitor.  Ann Rheum Dis. 1995;  54 (8) 662-669
    Google Scholar
  • 69 Mehraban F, Kuo S Y, Riera H, Chang C, Moskowitz R W. Prostromelysin and procollagenase genes are differentially up-regulated in chondrocytes from the knees of rabbits with experimental osteoarthritis.  Arthritis Rheum. 1994;  37 (8) 1189-1197
    Google Scholar
  • 70 Panula H E, Lohmander L S, Rönkkö S, Agren U, Helminen H J, Kiviranta I. Elevated levels of synovial fluid PLA2, stromelysin (MMP-3) and TIMP in early osteoarthrosis after tibial valgus osteotomy in young beagle dogs.  Acta Orthop Scand. 1998;  69 (2) 152-158
    Google Scholar
  • 71 Cook J L, Anderson C C, Kreeger J M, Tomlinson J L. Effects of human recombinant interleukin-1beta on canine articular chondrocytes in three-dimensional culture.  Am J Vet Res. 2000;  61 (7) 766-770
    Google Scholar
  • 72 Ratcliffe A, Beauvais P J, Saed-Nejad F, Shurety W, Caterson B. Synovial fluid analyses detect and differentiate proteoglycan metabolism in canine experimental models of osteoarthritis and disuse atrophy.  Agents Actions Suppl. 1993;  39 63-67
    Google Scholar
  • 73 Lindhorst E, Vail T P, Guilak F et al.. Longitudinal characterization of synovial fluid biomarkers in the canine meniscectomy model of osteoarthritis.  J Orthop Res. 2000;  18 (2) 269-280
    Google Scholar
  • 74 Budsberg S C, Lenz M E, Thonar E J. Serum and synovial fluid concentrations of keratan sulfate and hyaluronan in dogs with induced stifle joint osteoarthritis following cranial cruciate ligament transection.  Am J Vet Res. 2006;  67 (3) 429-432
    Google Scholar
  • 75 Innes J F, Sharif M, Barr A R. Relations between biochemical markers of osteoarthritis and other disease parameters in a population of dogs with naturally acquired osteoarthritis of the genual joint.  Am J Vet Res. 1998;  59 (12) 1530-1536
    Google Scholar
  • 76 Müller G, Michel A, Altenburg E. COMP (cartilage oligomeric matrix protein) is synthesized in ligament, tendon, meniscus, and articular cartilage.  Connect Tissue Res. 1998;  39 (4) 233-244
    Google Scholar
  • 77 Arai K, Tagami M, Hatazoe T et al.. Analysis of cartilage oligomeric matrix protein (COMP) in synovial fluid, serum and urine from 51 racehorses with carpal bone fracture.  J Vet Med Sci. 2008;  70 (9) 915-921
    Google Scholar
  • 78 Misumi K, Vilim V, Hatazoe T et al.. Serum level of cartilage oligomeric matrix protein (COMP) in equine osteoarthritis.  Equine Vet J. 2002;  34 (6) 602-608
    Google Scholar
  • 79 Chu Q, Lopez M, Hayashi K et al.. Elevation of a collagenase generated type II collagen neoepitope and proteoglycan epitopes in synovial fluid following induction of joint instability in the dog.  Osteoarthritis Cartilage. 2002;  10 (8) 662-669
    Google Scholar
  • 80 Goranov N V. Serum markers of lipid peroxidation, antioxidant enzymatic defense, and collagen degradation in an experimental (Pond-Nuki) canine model of osteoarthritis.  Vet Clin Pathol. 2007;  36 (2) 192-195
    Google Scholar
  • 81 Hayashi K, Kim S Y, Lansdowne J L, Kapatkin A, Déjardin L M. Evaluation of a collagenase generated osteoarthritis biomarker in naturally occurring canine cruciate disease.  Vet Surg. 2009;  38 (1) 117-121
    Google Scholar
  • 82 Carney S L, Billingham M E, Caterson B et al.. Changes in proteoglycan turnover in experimental canine osteoarthritic cartilage.  Matrix. 1992;  12 (2) 137-147
    Google Scholar
  • 83 Caterson B, Mahmoodian F, Sorrell J M et al.. Modulation of native chondroitin sulphate structure in tissue development and in disease.  J Cell Sci. 1990;  97 (Pt 3) 411-417
    Google Scholar
  • 84 Sorrell J M, Mahmoodian F, Schafer I A, Davis B, Caterson B. Identification of monoclonal antibodies that recognize novel epitopes in native chondroitin/dermatan sulfate glycosaminoglycan chains: their use in mapping functionally distinct domains of human skin.  J Histochem Cytochem. 1990;  38 (3) 393-402
    Google Scholar
  • 85 Ratcliffe A, Shurety W, Caterson B. The quantitation of a native chondroitin sulfate epitope in synovial fluid lavages and articular cartilage from canine experimental osteoarthritis and disuse atrophy.  Arthritis Rheum. 1993;  36 (4) 543-551
    Google Scholar
  • 86 Visco D M, Johnstone B, Hill M A, Jolly G A, Caterson B. Immunohistochemical analysis of 3-B-(-) and 7-D-4 epitope expression in canine osteoarthritis.  Arthritis Rheum. 1993;  36 (12) 1718-1725
    Google Scholar
  • 87 Johnson K A, Hay C W, Chu Q, Roe S C, Caterson B. 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 (6) 775-781
    Google Scholar
  • 88 Nganvongpanit K, Itthiarbha A, Ong-Chai S, Kongtawelert P. Evaluation of serum chondroitin sulfate and hyaluronan: biomarkers for osteoarthritis in canine hip dysplasia.  J Vet Sci. 2008;  9 (3) 317-325
    Google Scholar
  • 89 Hay C W, Chu Q, Budsberg S C, Clayton M K, Johnson K A. 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 (9) 1027-1032
    Google Scholar
  • 90 de Bruin T, de Rooster H, van Bree H, Cox E. Interleukin-8 mRNA expression in synovial fluid of canine stifle joints with osteoarthritis.  Vet Immunol Immunopathol. 2005;  108 (3-4) 387-397
    Google Scholar
  • 91 Yuan G H, Masuko-Hongo K, Sakata M et al.. The role of C-C chemokines and their receptors in osteoarthritis.  Arthritis Rheum. 2001;  44 (5) 1056-1070
    Google Scholar
  • 92 Rollins B J. Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease.  Mol Med Today. 1996;  2 (5) 198-204
    Google Scholar
  • 93 Mahn M M, Cook J L, Cook C R, Balke M T. Arthroscopic verification of ultrasonographic diagnosis of meniscal pathology in dogs.  Vet Surg. 2005;  34 (4) 318-323
    Google Scholar
  • 94 Breshears L A, Cook J L, Stoker A M, Fox D B, Luther J K. The Effect of Uniaxial Cyclic Tensile Load on Gene Expression in Canine Cranial Cruciate Ligamentocytes.  Vet Surg. 2010;  39 (4) 433-443
    Google Scholar
  • 95 Yoshimura T, Robinson E A, Tanaka S, Appella E, Kuratsu J, Leonard E J. Purification and amino acid analysis of two human glioma-derived monocyte chemoattractants.  J Exp Med. 1989;  169 (4) 1449-1459
    Google Scholar
  • 96 Matsushima K, Larsen C G, DuBois G C, Oppenheim J J. Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line.  J Exp Med. 1989;  169 (4) 1485-1490
    Google Scholar
  • 97 Yoshimura T, Robinson E A, Tanaka S, Appella E, Leonard E J. Purification and amino acid analysis of two human monocyte chemoattractants produced by phytohemagglutinin-stimulated human blood mononuclear leukocytes.  J Immunol. 1989;  142 (6) 1956-1962
    Google Scholar
  • 98 Carr M W, Roth S J, Luther E, Rose S S, Springer T A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant.  Proc Natl Acad Sci U S A. 1994;  91 (9) 3652-3656
    Google Scholar
  • 99 Taub D D, Proost P, Murphy W J et al.. Monocyte chemotactic protein-1 (MCP-1), -2, and -3 are chemotactic for human T lymphocytes.  J Clin Invest. 1995;  95 (3) 1370-1376
    Google Scholar
  • 100 Koch A E, Kunkel S L, Harlow L A et al.. Enhanced production of monocyte chemoattractant protein-1 in rheumatoid arthritis.  J Clin Invest. 1992;  90 (3) 772-779
    Google Scholar
  • 101 Stankovic A, Slavic V, Stamenkovic B, Kamenov B, Bojanovic M, Mitrovic D R. Serum and synovial fluid concentrations of CCL2 (MCP-1) chemokine in patients suffering rheumatoid arthritis and osteoarthritis reflect disease activity.  Bratisl Lek Listy (Tlacene Vyd). 2009;  110 (10) 641-646
    Google Scholar
  • 102 Seitz M, Loetscher P, Dewald B, Towbin H, Ceska M, Baggiolini M. Production of interleukin-1 receptor antagonist, inflammatory chemotactic proteins, and prostaglandin E by rheumatoid and osteoarthritic synoviocytes—regulation by IFN-gamma and IL-4.  J Immunol. 1994;  152 (4) 2060-2065
    Google Scholar
  • 103 Duffy A L, Olea-Popelka F J, Eucher J, Rice D M, Dow S W. Serum concentrations of monocyte chemoattractant protein-1 in healthy and critically ill dogs.  Vet Clin Pathol. 2010;  39 (3) 302-305
    Google Scholar
  • 104 Moser B, Clark-Lewis I, Zwahlen R, Baggiolini M. Neutrophil-activating properties of the melanoma growth-stimulatory activity.  J Exp Med. 1990;  171 (5) 1797-1802
    Google Scholar
  • 105 Lin M, Carlson E, Diaconu E, Pearlman E. CXCL1/KC and CXCL5/LIX are selectively produced by corneal fibroblasts and mediate neutrophil infiltration to the corneal stroma in LPS keratitis.  J Leukoc Biol. 2007;  81 (3) 786-792
    Google Scholar
  • 106 Fujiwara K, Ohkawara S, Takagi K, Yoshinaga M, Matsukawa A. Involvement of CXC chemokine growth-related oncogene-alpha in monosodium urate crystal-induced arthritis in rabbits.  Lab Invest. 2002;  82 (10) 1297-1304
    Google Scholar
  • 107 Modi W S, Yoshimura T. Isolation of novel GRO genes and a phylogenetic analysis of the CXC chemokine subfamily in mammals.  Mol Biol Evol. 1999;  16 (2) 180-193
    Google Scholar
  • 108 Remick D G, DeForge L E, Sullivan J F, Showell H J. Profile of cytokines in synovial fluid specimens from patients with arthritis. Interleukin 8 (IL-8) and IL-6 correlate with inflammatory arthritides.  Immunol Invest. 1992;  21 (4) 321-327
    Google Scholar
  • 109 Brennan F M, Zachariae C O, Chantry D et al.. Detection of interleukin 8 biological activity in synovial fluids from patients with rheumatoid arthritis and production of interleukin 8 mRNA by isolated synovial cells.  Eur J Immunol. 1990;  20 (9) 2141-2144
    Google Scholar
  • 110 Straubinger R K, Straubinger A F, Härter L et al.. Borrelia burgdorferi migrates into joint capsules and causes an up-regulation of interleukin-8 in synovial membranes of dogs experimentally infected with ticks.  Infect Immun. 1997;  65 (4) 1273-1285
    Google Scholar
  • 111 Straubinger R K, Straubinger A F, Summers B A, Erb H N, Härter L, Appel M J. Borrelia burgdorferi induces the production and release of proinflammatory cytokines in canine synovial explant cultures.  Infect Immun. 1998;  66 (1) 247-258
    Google Scholar
  • 112 Straubinger R K, Straubinger A F, Summers B A, Jacobson R H, Erb H N. Clinical manifestations, pathogenesis, and effect of antibiotic treatment on Lyme borreliosis in dogs.  Wien Klin Wochenschr. 1998;  110 (24) 874-881
    Google Scholar
  • 113 Merz D, Liu R, Johnson K, Terkeltaub R. IL-8/CXCL8 and growth-related oncogene alpha/CXCL1 induce chondrocyte hypertrophic differentiation.  J Immunol. 2003;  171 (8) 4406-4415
    Google Scholar
  • 114 Ko Y C, Mukaida N, Ishiyama S et al.. Elevated interleukin-8 levels in the urine of patients with urinary tract infections.  Infect Immun. 1993;  61 (4) 1307-1314
    Google Scholar
  • 115 Zaki MelS. Interleukin 8 is a surrogate marker for rapid diagnosis of bacteriuria.  Immunol Invest. 2008;  37 (7) 694-703
    Google Scholar
  • 116 Taha A S, Grant V, Kelly R W. Urinalysis for interleukin-8 in the non-invasive diagnosis of acute and chronic inflammatory diseases.  Postgrad Med J. 2003;  79 (929) 159-163
    Google Scholar
  • 117 Ling S M, Patel D D, Garnero P et al.. Serum protein signatures detect early radiographic osteoarthritis.  Osteoarthritis Cartilage. 2009;  17 (1) 43-48
    Google Scholar
  • 118 Pulsatelli L, Dolzani P, Piacentini A et al.. Chemokine production by human chondrocytes.  J Rheumatol. 1999;  26 (9) 1992-2001
    Google Scholar

Bridget GarnerD.V.M. Ph.D. 

Department of Veterinary Pathology, University of Georgia

501 DW Brooks Drive, Athens, GA 30605

Email: garnerb@uga.edu

      >