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- Lark, Michael W., et al.
(författare)
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Aggrecan degradation in human cartilage : Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints
- 1997
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 100:1, s. 93-106
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Tidskriftsartikel (refereegranskat)abstract
- To examine the activity of matrix metalloproteinases (MMPs) and aggrecanase in control and diseased human articular cartilage, metabolic fragments of aggrecan were detected with monospecific antipeptide antibodies. The distribution and quantity of MMP-generated aggrecan G1 fragments terminating in VDIPEN341 were compared with the distribution of aggrecanase-generated G1 fragments terminating in NITEGE373. Both types of G1 fragments were isolated from osteoarthritic cartilage. The sizes were consistent with a single enzymatic cleavage in the interglobular domain region, with no further proteolytic processing of these fragments. Both neoepitopes were also detected by immunohistochemistry in articular cartilage from patients undergoing joint replacement for osteoarthritis (OA), rheumatoid arthritis (RA), and in cartilage from adults with no known joint disease. In control specimens, the staining intensity for both G1 fragments increased with age, with little staining in cartilage from 22-wk-old fetal samples. There was also an increase with age in the extracted amount of MMP- generated neoepitope in relation to both aggrecan and collagen content, confirming the immunohistochemical results. After the age of 20-30 yr this relationship remained at a steady state. The staining for the MMP-generated epitope was most marked in control cartilage exhibiting histological signs of damage, whereas intense staining for the aggrecanase-generated fragment was often noted in adult cartilage lacking overt histological damage. Intense staining for both neoepitopes appeared in the more severely fibrillated, superficial region of the tissue. Intense immunostaining for both VDIPEN- and NITEGE-neoepitopes was also detected in joint cartilage from patients with OA or RA. Cartilage in these specimens was significantly more degraded and high levels of staining for both epitopes was always seen in areas with extensive cartilage damage. The levels of extracted VDIPEN neoepitope relative to collagen or aggrecan in both OA and RA samples were similar to those seen in age-matched control specimens. Immunostaining for both types of aggrecan fragments was seen surrounding the cells but also further removed in the interterritorial matrix. In some regions of the tissue, both neoepitopes were found while in others only one was detected. Thus, generation and/or turnover of these specific catabolic aggrecan fragments is not necessarily coordinated. Our results are consistent with the presence in both normal and arthritic joint cartilage of proteolytic activity against aggrecan based on both classical MMPs and 'aggrecanase'.
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| 2. |
- Lark, Michael W., et al.
(författare)
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Aggrecan degradation in osteoarthritis and rheumatoid arthritis
- 1995
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Ingår i: Acta Orthopaedica. - : Informa UK Limited. - 1745-3674 .- 0001-6470. ; 66:S266, s. 92-97
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Tidskriftsartikel (refereegranskat)abstract
- Aggrecan turnover is critically important to maintain extracellular matrix homeostasis in articular cartilage. Cartilage aggrecan metabolism has been studied in chondrocyte cell cultures, cartilage explant cultures, and in whole animal models. In many of these studies, matrix metalloproteinases (MMPs) are proposed to degrade cartilage aggrecan. MMP expression appears elevated in joint tissues from patients with osteoarthritis (OA) and rheumatoid arthritis (RA) (Dean et al. 1989, Wolfe et al. 1993) and inhibitors of both MMPs and thiol proteinases have been shown to block aggrecan (Buttle et al. 1992) and type II collagen (Mort et al. 1993) degradation in cartilage explant cultures. Using antibodies and cDNA probes, elevations in expression and concentration of many of these enzymes in animal models and in OA and RA have been described. Human cartilage aggrecan has now been cloned and sequenced (Doege et al. 1991). This information, in combination with the ability to sequence aggrecan and aggrecan fragments at the protein level, has resulted in the identification of several aggrecan fragments which appear to result from proteinase degradation. In this report, we describe data which suggest that MMPs may in part be responsible for aggrecan catabolism in normal articular cartilage, as well as in the elevated catabolism seen in OA and RA.
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| 3. |
- Lohmander, L. Stefan, et al.
(författare)
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Cartilage matrix metabolism in osteoarthritis : markers in synovial fluid, serum, and urine
- 1992
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Ingår i: Clinical Biochemistry. - 0009-9120. ; 25:3, s. 167-174
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Tidskriftsartikel (refereegranskat)abstract
- Osteoarthritis is a major cause of disability and early retirement. Yet we lack the means to diagnose the disease in its early stages or to monitor the effects of treatment on the target tissue, the joint cartilage. Neither can we identify the disease mechanisms at the tissue or cell level. Current research focuses on the use of markers of cartilage matrix metabolism in body fluids as a means to diagnose and monitor osteoarthritis. Cartilage proteoglycan, collagen and glycoprotein fragments, as well as proteinases and their inhibitors, are being suggested for this purpose. Structural information on matrix molecule fragments released into body fluids may also help to identify the enzymes active in the destruction of the cartilage, a central issue in osteoarthritis.
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| 4. |
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| 5. |
- Lohmander, L. Stefan, et al.
(författare)
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Metalloproteinases, tissue inhibitor, and proteoglycan fragments in knee synovial fluid in human osteoarthritis
- 1993
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Ingår i: Arthritis and Rheumatism. - 0004-3591. ; 36:2, s. 181-189
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine the concentrations of human stromelysin-1, collagenase, tissue inhibitor of metalloproteinases (TIMP), and proteoglycan fragments in knee synovial fluid in patients with injury to the meniscus or anterior cruciate ligament, posttraumatic osteoarthritis, primary osteoarthritis, or pyrophosphate arthritis. Methods. Synovial fluid samples were collected from patients with knee disease diagnosed arthroscopically and radiologically. Concentrations of stromelysin-1, collagenase, and TIMP-1 were determined by sandwich immunoassay, using monoclonal and polyclonal antibodies. Fragments of cartilage proteoglycan containing the chondroitin sulfate-binding region were determined by immunoassay with a polyclonal antibody. Results. Average concentrations of metalloproteinases, TIMP, and proteoglycan fragments in joint fluid were significantly elevated in patients from all disease groups as compared with volunteers with healthy knees (reference group). Stromelysin concentrations in disease groups averaged 15-45 times that of the reference group. The molar ratios between stromelysin and collagenase varied between 10 and 150. The molar ratio between total stromelysin and free TIMP was 0.5 in the reference group and between 1.6 and 5.3 in the disease groups. Conclusion. Stromelysin concentration in joint fluid is a parameter that distinguishes diseased joints from healthy joints, with a sensitivity of 84% and a specificity of 90%. The high concentrations of metalloproteinase relative to TIMP in joint fluid from patients with the conditions studied may be associated with cartilage matrix degradation in these arthritides.
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| 6. |
- Lohmander, L. S., et al.
(författare)
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Temporal patterns of stromelysin-1, tissue inhibitor, and proteoglycan fragments in human knee joint fluid after injury to the cruciate ligament or meniscus
- 1994
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Ingår i: Journal of Orthopaedic Research. - 0736-0266. ; 12:1, s. 21-28
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Tidskriftsartikel (refereegranskat)abstract
- Stromelysin-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and proteoglycan fragments were quantified in knee synovial fluid samples in a cross-sectional study of patients who had injury to the anterior cruciate ligament or the meniscus. The average concentrations of stromelysin-1 and TIMP-1 increased 25-fold and 10-fold within the first day after the trauma, respectively, and the concentration of proteoglycan fragments increased 4- fold. From approximately 1-6 months after injury, the levels of these markers were higher after injury to the cruciate ligament than after injury to the meniscus. From 6 months to 18 years after trauma, however, the levels of stromelysin-1 and TIMP-1 in patients who had an injury to the ligament were the same as the levels in patients who had a meniscal lesion, but the levels were increased compared with those for a reference group of healthy volunteers. The molar balance of stromelysin-1 to TIMP-1 in synovial fluid in both groups of injured joints changed from a balance representing an excess of free inhibitor in the normal joint to one representing an excess of free enzyme in the injured joint. The increased release of these markers to joint fluid both early and late after trauma may be caused by a change in the loading patterns in the knee with an injured ligament or meniscus or by synovitis induced by bleeding. The increased release may be associated with the frequent development of posttraumatic osteoarthritis in patients with these injuries.
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| 7. |
- Roos, Harald, et al.
(författare)
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Markers of cartilage matrix metabolism in human joint fluid and serum : the effect of exercise
- 1995
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Ingår i: Osteoarthritis and Cartilage. - 1063-4584 .- 1522-9653. ; 3:1, s. 7-14
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Tidskriftsartikel (refereegranskat)abstract
- The concentrations of cartilage proteoglycan (aggrecan), stromelysin-1, tissue inhibitor of metalloproteinases-1 (TIMP-1) and procollagen II C-propeptide in knee joint fluid and the levels of aggrecan, hyaluronan and keratan sulfate in serum were measured before and after exercise in 33 healthy athletes. The samples before exercise were obtained after 24 h rest from running or soccer and the samples after exercise were obtained 30-60 min after the exercise. Nine athletes ran on a treadmill for 60 min, 16 ran on road for 80 min and 8 played one soccer game (90 min). A reference group of 28 patients with knee pain but not evidence of joint pathology or injury was used for comparison. In joint fluid no single marker from the degradative processes in cartilage matrix changed significantly with exercise but all showed a rising trend. All markers except stromelysin showed lower concentrations in athletes at rest compared to the reference group. In serum from runners before exercise the concentration of keratan sulfate was significantly higher than in both the soccer and reference groups and further increased after exercise. The increase in markers after exercise may reflect an effect of mechanical loading in combination with a possible high turnover rate of body cartilage matrix in these individuals.
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