Induction of osteoarthritis in the rat by surgical tear of the meniscus: Inhibition of joint damage by a matrix metalloproteinase inhibitor.

OBJECTIVE Characterize a model of osteoarthritis (OA) induced by a surgically transecting the medial collateral ligament and meniscus. Evaluate the effectiveness of a matrix metalloproteinase (MMP) inhibitor in this model. METHODS The medial collateral ligament of the right knee of rats was transected and a single full thickness cut was made through meniscus. Rats were sacrificed at various times after the surgery to assess the severity of gross cartilage damage using an image analyser and microscopically by histology. The effect of an MMP inhibitor in this model was assessed by administering compound twice daily for the 21 days and evaluating gross and histological joint damage at day 21. The in vitro potency of the MMP inhibitor (MMPI) against a panel of human recombinant MMPs was assessed kinetically using a quenched fluorescent substrate. RESULTS Surgical transection of the medial collateral ligament and meniscus resulted in a time dependent increase in the severity of the cartilage lesion (depth) as measured histologically but only a slight increase in the area of the lesion as assessed grossly by image analysis. Administration of a MMPI orally twice daily (b.i.d.) at 25mg/kg to rats in the meniscal tear model resulted in significant inhibition of cartilage degradation and osteophyte formation (total joint score) of 39+/-7% (mean+/-S.E.M., from four separate experiments). CONCLUSION These results demonstrate that MMP inhibition is effective in reducing the joint damage that occurs in the meniscal tear model of OA and support a potential therapeutic role for MMP inhibition in the treatment of human OA.

[1]  T. Hardingham,et al.  The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B. , 1992, The Journal of biological chemistry.

[2]  M. Lark,et al.  Identification of a stromelysin cleavage site within the interglobular domain of human aggrecan. Evidence for proteolysis at this site in vivo in human articular cartilage. , 1992, The Journal of biological chemistry.

[3]  M. Natchus,et al.  Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors. , 1999, Journal of medicinal chemistry.

[4]  C. Rorabeck,et al.  Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. , 1997, The Journal of clinical investigation.

[5]  R. Moskowitz,et al.  Experimentally induced degenerative joint lesions following partial meniscectomy in the rabbit. , 1973, Arthritis and rheumatism.

[6]  L. Lohmander,et al.  Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis. , 1993, Arthritis and rheumatism.

[7]  R. Mason,et al.  Matrix metalloproteinases and aggrecanases cleave aggrecan in different zones of normal cartilage but colocalize in the development of osteoarthritic lesions in STR/ort mice. , 2001, Arthritis and rheumatism.

[8]  E. J. Lewis,et al.  Ro 32-3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis. , 1998, Arthritis and rheumatism.

[9]  O. Svensson,et al.  Effect of an Inhibitor of Matrix Metalloproteinases on Spontaneous Osteoarthritis in Guinea Pigs , 1998, Advances in dental research.

[10]  C. Little,et al.  Histomorphological and immunohistochemical evaluation of joint changes in a model of osteoarthritis induced by lateral meniscectomy in sheep. , 1997, The Journal of rheumatology.

[11]  A. Barrett,et al.  Inhibition of cartilage proteoglycan release by a specific inactivator of cathepsin B and an inhibitor of matrix metalloproteinases. Evidence for two converging pathways of chondrocyte-mediated proteoglycan degradation. , 1993, Arthritis and rheumatism.

[12]  R. Wynn,et al.  Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. , 1999, Science.

[13]  R. Wynn,et al.  Cloning and Characterization of ADAMTS11, an Aggrecanase from the ADAMTS Family* , 1999, The Journal of Biological Chemistry.

[14]  G Murphy,et al.  A novel coumarin‐labelled peptide for sensitive continuous assays of the matrix metalloproteinases , 1992, FEBS letters.

[15]  T. Hardingham,et al.  Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain. , 1993, The Biochemical journal.

[16]  J. Pelletier,et al.  Collagenase-3 (matrix metalloprotease 13) is preferentially localized in the deep layer of human arthritic cartilage in situ: in vitro mimicking effect by transforming growth factor beta. , 1997, Arthritis and rheumatism.

[17]  D. Woolley,et al.  Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. , 2001, Arthritis and rheumatism.

[18]  I. Otterness,et al.  Collagenase 1 and collagenase 3 expression in a guinea pig model of osteoarthritis. , 1998, Arthritis and rheumatism.

[19]  R. Altman,et al.  Collagenolytic activity and collagen matrix breakdown of the articular cartilage in the Pond-Nuki dog model of osteoarthritis. , 1983, Arthritis and rheumatism.

[20]  J. Pelletier,et al.  Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. , 1989, The Journal of clinical investigation.

[21]  A. Bendele,et al.  Effects of body weight restriction on the development and progression of spontaneous osteoarthritis in guinea pigs. , 1991, Arthritis and rheumatism.

[22]  G. Ciszewski,et al.  Potent and selective carboxylic acid-based inhibitors of matrix metalloproteinases. , 2001, Journal of medicinal chemistry.

[23]  L. Lohmander,et al.  The structure of aggrecan fragments in human synovial fluid. Evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis. , 1993, Arthritis and rheumatism.

[24]  R. Moskowitz,et al.  Prostromelysin and procollagenase genes are differentially up-regulated in chondrocytes from the knees of rabbits with experimental osteoarthritis. , 1994, Arthritis and rheumatism.

[25]  A. Bendele,et al.  Animal Models of Arthritis: Relevance to Human Disease , 1999, Toxicologic pathology.

[26]  D. A. Brandt,et al.  Reduction of the severity of canine osteoarthritis by prophylactic treatment with oral doxycycline. , 1992, Arthritis and rheumatism.

[27]  A. Bendele.  Progressive Chronic Osteoarthritis in Femorotibial Joints of Partial Medial Meniscectomized Guinea Pigs , 1987, Veterinary pathology.

[28]  A. Freemont,et al.  Moderation of iodoacetate-induced experimental osteoarthritis in rats by matrix metalloproteinase inhibitors. , 2001, Osteoarthritis and cartilage.

[29]  L. Lohmander,et al.  The structure of aggrecan fragments in human synovial fluid. Evidence for the involvement in osteoarthritis of a novel proteinase which cleaves the Glu 373-Ala 374 bond of the interglobular domain. , 1992, The Journal of clinical investigation.

[30]  J. Pelletier,et al.  Coordinate synthesis of stromelysin, interleukin-1, and oncogene proteins in experimental osteoarthritis. An immunohistochemical study. , 1993, The American journal of pathology.

[31]  B. Caterson,et al.  Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase. , 1998, Osteoarthritis and cartilage.

[32]  K. Geoghegan,et al.  Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. , 1996, The Journal of clinical investigation.

[33]  G. Nuki,et al.  Experimentally-induced osteoarthritis in the dog. , 1973, Annals of the rheumatic diseases.

[34]  A. Hollander,et al.  Type II collagen degradation in articular cartilage fibrillation after anterior cruciate ligament transection in rats. , 2001, Osteoarthritis and cartilage.

[35]  H. Roos,et al.  Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. , 1995, Osteoarthritis and cartilage.

[36]  K. Brandt,et al.  Oral administration of doxycycline reduces collagenase and gelatinase activities in extracts of human osteoarthritic cartilage. , 1998, The Journal of rheumatology.

[37]  A. Bendele,et al.  Early Histopathologic and Ultrastructural Alterations in Femorotibial Joints of Partial Medial Meniscectomized Guinea Pigs , 1987, Veterinary pathology.

[38]  A. Hollander,et al.  Differences in type II collagen degradation between peripheral and central cartilage of rat stifle joints after cranial cruciate ligament transection. , 2000, Arthritis and rheumatism.