The release of crosslinked peptides from type II collagen into human synovial fluid is increased soon after joint injury and in osteoarthritis.

OBJECTIVE To determine concentrations of crosslinked C-telopeptide fragments of type II collagen (CTX-II) in synovial fluid (SF) from patients with joint injury, osteoarthritis (OA), or other knee arthritides. METHODS Two study groups were used: a cross-sectional group, which included healthy-knee volunteers (reference group [REF]) and patients with pseudogout (PPA), an anterior cruciate ligament tear with or without a meniscus tear (INJ), or primary knee OA (POA); and a longitudinal group, which included patients with arthroscopic cartilage changes or septic arthritis. CTX-II was quantified by competition enzyme-linked immunosorbent assay (ELISA) based on a monoclonal antibody that recognized the C-terminus of the peptide EKGPDP as a proteolytic neoepitope. Aggrecan fragments, matrix metalloproteinases 1 and 3, and tissue inhibitor of metalloproteinases 1 were determined by ELISAs. RESULTS Concentrations of CTX-II in SF were higher in patients with PPA, INJ, and POA than in the REF group (P < 0.001). After joint injury, mean levels of CTX-II in SF were increased above REF levels at all time intervals (P < 0.001), and were highest within hours after trauma. In those in the longitudinal study group with joint cartilage damage, variation coefficients for CTX-II were 81% (between patients) and 64% (within patient), monitored over 1 year. In a patient with septic arthritis, SF CTX-II increased at the onset of symptoms, and peaked 30-fold higher than the baseline. Concentrations of all biomarkers decreased with successful treatment. CONCLUSION This is the first report to describe the release into SF of soluble molecular fragments specific for the degradation of mature, crosslinked, type II collagen (CII) in human OA and joint injury. The results provide strong evidence that the integrity of the CII network of cartilage is compromised soon after joint injury and in arthritis. This early degradation of CII may represent an important treatment target.

[1]  D. Heinegård,et al.  Release of cartilage oligomeric matrix protein (COMP) into joint fluid after knee injury and in osteoarthritis. , 1994, Annals of the rheumatic diseases.

[2]  S. Lohmander.  Turnover of proteoglycans in guinea pig costal cartilage. , 1977, Archives of biochemistry and biophysics.

[3]  Gene expression of collagen types IIA and IX correlates with ultrastructural events in early osteoarthrosis: new applications of the rabbit meniscectomy model. , 1997, The Journal of rheumatology.

[4]  A. Poole,et al.  Changes in joint cartilage aggrecan after knee injury and in osteoarthritis. , 1999, Arthritis and rheumatism.

[5]  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.

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

[7]  D. Eyre,et al.  Biosynthesis of collagen and other matrix proteins by articular cartilage in experimental osteoarthrosis. , 1980, The Biochemical journal.

[8]  L. Ryd,et al.  Intraarticular injections of hyaluronan in patients with cartilage abnormalities and knee pain. A one-year double-blind, placebo-controlled study. , 1994, Arthritis and rheumatism.

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

[10]  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.

[11]  L Ryd,et al.  Proteoglycan fragments in joint fluid. Influence of arthrosis and inflammation. , 1992, Acta orthopaedica Scandinavica.

[12]  C. Rorabeck,et al.  Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. , 1995, The Journal of clinical investigation.

[13]  Lohmander Ls,et al.  Articular cartilage and osteoarthrosis. The role of molecular markers to monitor breakdown, repair and disease. , 1994 .

[14]  J. E. Bassett,et al.  Cartilage matrix molecules in serum and synovial fluid. , 1995, Current opinion in rheumatology.

[15]  T. Aigner,et al.  Isolation of RNA from small human articular cartilage specimens allows quantification of mRNA expression levels in local articular cartilage defects , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[16]  Brandt Kd,et al.  Hypertrophic repair of canine articular cartilage in osteoarthritis after anterior cruciate ligament transection. , 1991 .

[17]  C. Rorabeck,et al.  Increased damage to type II collagen in osteoarthritic articular cartilage detected by a new immunoassay. , 1994, The Journal of clinical investigation.

[18]  L. Ryd,et al.  Increased levels of proteoglycan fragments in knee joint fluid after injury. , 1989, Arthritis and rheumatism.

[19]  J. Pelletier,et al.  The new collagenase, collagenase-3, is expressed and synthesized by human chondrocytes but not by synoviocytes. A role in osteoarthritis. , 1996, The Journal of clinical investigation.

[20]  I. Otterness,et al.  Detection of collagenase-induced damage of collagen by 9A4, a monoclonal C-terminal neoepitope antibody. , 1999, Matrix biology : journal of the International Society for Matrix Biology.

[21]  A. Poole,et al.  Early degradation of type IX and type II collagen with the onset of experimental inflammatory arthritis. , 2001, Arthritis and rheumatism.

[22]  D. Zukor,et al.  Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. , 2002, Arthritis and rheumatism.

[23]  I. Otterness,et al.  An analysis of 14 molecular markers for monitoring osteoarthritis: segregation of the markers into clusters and distinguishing osteoarthritis at baseline. , 2000, Osteoarthritis and cartilage.

[24]  P. Qvist,et al.  Collagen type II C-telopeptide fragments as an index of cartilage degradation. , 2001, Bone.

[25]  A. Ratcliffe,et al.  Changes in proteoglycan turnover in experimental canine osteoarthritic cartilage. , 1992, Matrix.

[26]  A. Hollander,et al.  Degradation of cartilage type II collagen precedes the onset of osteoarthritis following anterior cruciate ligament rupture. , 1999, Arthritis and rheumatism.

[27]  D. Eyre.  Articular cartilage and changes in Arthritis: Collagen of articular cartilage , 2001, Arthritis research.

[28]  I. Palacios,et al.  High-resolution MRI detects cartilage swelling at the early stages of experimental osteoarthritis. , 2001, Osteoarthritis and cartilage.

[29]  T. Koob,et al.  Early changes in material properties of rabbit articular cartilage after meniscectomy , 1983, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[30]  H. Muir,et al.  Biochemical changes in the cartilage of the knee in experimental and natural osteoarthritis in the dog. , 1976, The Journal of bone and joint surgery. British volume.

[31]  E. Thonar,et al.  Markers of cartilage matrix metabolism in human joint fluid and serum: the effect of exercise. , 1995, Osteoarthritis and cartilage.

[32]  L. Ryd,et al.  Candida albicans arthritis in a nonimmunocompromised patient. Complication of placebo intraarticular injections. , 1993, Acta orthopaedica Scandinavica.

[33]  H. Roos,et al.  A longitudinal study of cartilage matrix metabolism in patients with cruciate ligament rupture--synovial fluid concentrations of aggrecan fragments, stromelysin-1 and tissue inhibitor of metalloproteinase-1. , 1994, British journal of rheumatology.

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

[35]  C. McDevitt,et al.  Cartilage content of an immature dog. , 1989, Connective tissue research.

[36]  P. Dieppe,et al.  Evidence for altered synthesis of type II collagen in patients with osteoarthritis. , 1998, The Journal of clinical investigation.

[37]  P. Delmas,et al.  Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[38]  J. Weidner,et al.  Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. , 1997, The Journal of clinical investigation.

[39]  I. Otterness,et al.  An analysis of 14 molecular markers for monitoring osteoarthritis. Relationship of the markers to clinical end-points. , 2001, Osteoarthritis and cartilage.

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

[41]  J. Mizrahi,et al.  The increased swelling and instantaneous deformation of osteoarthritic cartilage is highly correlated with collagen degradation. , 2000, Arthritis and rheumatism.

[42]  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.

[43]  N. Bhardwaj,et al.  Detection of stromelysin and collagenase in synovial fluid from patients with rheumatoid arthritis and posttraumatic knee injury. , 1992, Arthritis and rheumatism.

[44]  M. Markel,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. , 2002, Osteoarthritis and cartilage.

[45]  I. Otterness,et al.  Using Molecular Markers to Monitor Osteoarthritis , 2002 .

[46]  B Kurz,et al.  Biosynthetic response and mechanical properties of articular cartilage after injurious compression , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[47]  I. Otterness,et al.  Analysis of collagenase-cleavage of type II collagen using a neoepitope ELISA. , 2001, Journal of immunological methods.

[48]  F. Guilak,et al.  Simultaneous changes in the mechanical properties, quantitative collagen organization, and proteoglycan concentration of articular cartilage following canine meniscectomy , 2000, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[49]  C. Helmick,et al.  Serum cartilage oligomeric matrix protein and clinical signs and symptoms of potential pre-radiographic hip and knee pathology. , 2002, Osteoarthritis and cartilage.

[50]  H. Roos,et al.  Temporal patterns of stromelysin‐1, tissue inhibitor, and proteoglycan fragments in human knee joint fluid after injury to the cruciate ligament or meniscus , 1994, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[51]  H. Møller,et al.  ELISA for the core protein of the cartilage large aggregating proteoglycan, aggrecan: comparison with the concentrations of immunogenic keratan sulphate in synovial fluid, serum and urine. , 1994, Clinica chimica acta; international journal of clinical chemistry.

[52]  R. Maciewicz,et al.  Aggrecan is degraded by matrix metalloproteinases in human arthritis. Evidence that matrix metalloproteinase and aggrecanase activities can be independent. , 1996, The Journal of clinical investigation.

[53]  H. Roos,et al.  Procollagen II C-propeptide in joint fluid: changes in concentration with age, time after knee injury, and osteoarthritis. , 1996, The Journal of rheumatology.

[54]  G. Firestein,et al.  Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intraarticular corticosteroids. , 1991, Arthritis and rheumatism.

[55]  E. Thonar,et al.  Longitudinal and cross-sectional variability in markers of joint metabolism in patients with knee pain and articular cartilage abnormalities. , 1998, Osteoarthritis and cartilage.

[56]  J. V. van Meurs,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. , 1999, Arthritis and rheumatism.

[57]  S. Ahlback,et al.  Osteoarthrosis of the knee. A radiographic investigation. , 1968 .