| 1. |
- Dahlberg, Leif, et al.
(författare)
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Proteoglycan fragments in joint fluid : Influence of arthrosis and inflammation
- 1992
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 0001-6470. ; 63:4, s. 417-423
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Tidskriftsartikel (refereegranskat)abstract
- We determined the concentration of proteoglycan fragments in knee joint fluid collected from knee-ligament injured patients more than 6 months after the trauma and from patients with acute pyrophosphate arthritis and arthrosis or with arthrosis only. Injured patients with normal or only mildly altered cartilage at arthroscopy and with normal radiographs, had twice the average concentration of healthy volunteers. Other injured patients with advanced, radiographic signs of arthrosis, had synovial fluid proteoglycan fragment concentrations within the range of healthy volunteers. Patients with pyrophosphate arthritis had the highest concentrations, substantially increased compared with both arthrosis patients, with or without knee injury and healthy volunteers. Likewise, there was an inverse relation between the degree of arthrosis and the concentration of proteoglycan fragments in the joint fluid in patients with pyrophosphate arthritis and arthrosis or with arthrosis only. We conclude that synovial fluid levels of proteoglycan fragments are influenced by the mass of cartilage matrix remaining in the joint, the inflammatory activity in the joint, and the metabolic activity of the cartilage cells.
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| 2. |
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| 3. |
- Kraus, V. B., et al.
(författare)
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Application of biomarkers in the development of drugs intended for the treatment of osteoarthritis
- 2011
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Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 19:5, s. 515-542
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Osteoarthritis (OA) is a chronic and slowly progressive disease for which biomarkers may be able to provide a more rapid indication of therapeutic responses to therapy than is currently available; this could accelerate and facilitate OA drug discovery and development programs. The goal of this document is to provide a summary and guide to the application of in vitro (biochemical and other soluble) biomarkers in the development of drugs for OA and to outline and stimulate a research agenda that will further this goal. Methods: The Biomarkers Working Group representing experts in the field of OA biomarker research from both academia and industry developed this consensus document between 2007 and 2009 at the behest of the Osteoarthritis Research Society International Federal Drug Administration initiative (OARSI FDA initiative). Results: This document summarizes definitions and classification systems for biomarkers, the current outcome measures used in OA clinical trials, applications and potential utility of biomarkers for development of OA therapeutics, the current state of qualification of OA-related biomarkers, pathways for biomarker qualification, critical needs to advance the use of biomarkers for drug development, recommendations regarding practices and clinical trials, and a research agenda to advance the science of OA-related biomarkers. Conclusions: Although many OA-related biomarkers are currently available they exist in various states of qualification and validation. The biomarkers that are likely to have the earliest beneficial impact on clinical trials fall into two general categories, those that will allow targeting of subjects most likely to either respond and/or progress (prognostic value) within a reasonable and manageable time frame for a clinical study (for instance within 1-2 years for an OA trial), and those that provide early feedback for preclinical decision-making and for trial organizers that a drug is having the desired biochemical effect. As in vitro biomarkers are increasingly investigated in the context of specific drug treatments, advances in the field can be expected that will lead to rapid expansion of the list of available biomarkers with increasing understanding of the molecular processes that they represent. (C) 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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| 4. |
- Lohmander, L. Stefan, et al.
(författare)
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Increased concentrations of bone sialoprotein in joint fluid after knee injury
- 1996
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Ingår i: Annals of the Rheumatic Diseases. - 0003-4967. ; 55:9, s. 622-626
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Tidskriftsartikel (refereegranskat)abstract
- Objective - To detect evidence for localised changes in bone matrix metabolism after joint trauma and in post-traumatic osteoarthritis by quantification of bone sialoprotein in joint fluid and serum after knee injury in a cross sectional study. Methods - Samples of knee joint fluid and serum were obtained from volunteers with normal knees (n = 19), patients with rupture of the anterior cruciate ligament isolated or combined with tear of a meniscus (n = 114), and patients with isolated meniscus lesions (n = 80). Concentrations of bone sialoprotein were determined by ELISA. Concentrations of other markers of joint tissue metabolism in these samples were determined in previous investigations. Results - The median concentration of bone sialoprotein in joint fluid from healthy volunteers was 122 ng ml-1 (range 41 to 183). Concentrations of bone sialoprotein were increased in both injury groups compared with the reference group (median for cruciate ligament injury 146 ng ml-1, range 72 to 339; median for meniscus injury 166 ng ml-1, range 75 to 376). After injury, bone sialoprotein increased quickly and remained increased for six months. Bone sialoprotein in joint fluid was increased only in samples from joints with normal or nearly normal (fibrillated) cartilage, and was within reference range in joints with radiographic signs of osteoarthritis. Bone sialoprotein concentrations in joints with cruciate ligament injury were positively correlated with levels of aggrecan and cartilage oligomeric matrix protein fragments, and with levels of stromelysin-1 and tissue inhibitor of metalloproteinase-1. The ratios between the concentrations of bone sialoprotein in joint fluid and serum were >1 in the majority of the cruciate ligament injury cases. Conclusions - The release of significant amounts of bone sialoprotein into joint fluid in connection with acute joint trauma may be associated with injury to, and active remodelling of, the cartilage-bone interface and subchondral bone. The findings are consistent with dramatic shifts in cartilage, bone, and synovial metabolism following joint injury. Bone sialoprotein concentrations in synovial fluid may be a useful marker of subchondral injury and remodelling following joint injury.
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| 5. |
- Lohmander, Stefan, et al.
(författare)
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Increased levels of proteoglycan fragments in knee joint fluid after injury
- 1989
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 32:11, s. 1434-1442
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Tidskriftsartikel (refereegranskat)abstract
- We measured the levels of cartilage proteoglycan (PG) fragments in knee joint synovial fluid obtained from patients with previous trauma of the knee, early gonarthrosis, or pyrophosphate synovitis, and in age-matched control subjects. During the initial 3-4 weeks after rupture of the anterior cruciate ligament or the meniscus (confirmed by arthroscopy), markedly increased PG fragment levels were found. At later times after trauma (up to 4 years), many of these patients still had significantly elevated levels of cartilage PG fragments in the joint fluid. In a group of older patients with gonarthrosis, these levels were only moderately elevated, while in patients with acute pseudogout, greatly increased levels were observed. Although longitudinal studies are needed to validate the significance, PG fragments in joint fluid may be a marker for early posttraumatic arthrosis.
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| 6. |
- Maksymowych, Walter P., et al.
(författare)
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Development of draft validation criteria for a soluble biomarker to be regarded as a valid biomarker reflecting structural damage endpoints in rheumatoid arthritis and spondyloarthritis clinical trials
- 2007
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Ingår i: Journal of Rheumatology. - 0315-162X. ; 34:3, s. 634-640
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Recent work has shown that several soluble biomarkers, detectable in peripheral blood, synovial fluid, and/or urine, reflect remodeling of joint tissues and may therefore constitute outcome measures that reflect joint damage. Consequently, it is now desirable to begin the process of developing criteria for validation of a soluble biomarker as an outcome measure reflecting structural damage progression in trials of disease-modifying therapies for rheumatoid arthritis (RA) and spondyloarthritis (SpA). Our objective was to develop validation criteria for a soluble biomarker to be regarded as a valid biomarker reflecting radiological endpoints in RA and SpA clinical trials. Methods. A special interest group was established comprising investigators with expertise in soluble biomarker assay development as well as in outcomes research. This project was initiated by means of a Delphi consensus exercise. A list of draft criteria was first generated following a review of a US National Institutes of Health (NIH) 2000 white paper (available at: http://www.niams.nih.gov/ne/oi/ oabiomarwhipap.htm) that focused on biomarkers in OA, and these were organized under subject headings relevant to the OMERACT filter: truth, discrimination, and feasibility. Additional criteria were solicited from the working group. This was followed by 3 rounds of voting. Results. A list of 31 criteria was generated prior to voting. The first 2 rounds of voting resulted in cumulative agreement that 19 criteria be retained and 4 discarded, while discrepancies were recorded for 8 criteria. In the third round of voting, cumulative agreement was achieved to retain 5 of the 8 discrepant criteria, so that the final list included 24 criteria. Conclusion. A draft set of criteria for validation of a soluble biomarker to be regarded as reflecting radiological damage endpoints in clinical trials has been proposed on the basis of consensus.
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| 7. |
- Stattin, Eva-Lena, et al.
(författare)
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A missense mutation in the aggrecan C-type lectin domain disrupts extracellular matrix interactions and causes dominant familial osteochondritis dissecans
- 2010
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 86:2, s. 126-137
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Tidskriftsartikel (refereegranskat)abstract
- Osteochondritis dissecans is a disorder in which fragments of articular cartilage and subchondral bone dislodge from the joint surface. We analyzed a five-generation family in which affected members had autosomal-dominant familial osteochondritis dissecans. A genome-wide linkage analysis identified aggrecan (ACAN) as a prime candidate gene for the disorder. Sequence analysis of ACAN revealed heterozygosity for a missense mutation (c.6907G > A) in affected individuals, resulting in a p.V2303M amino acid substitution in the aggrecan G3 domain C-type lectin, which mediates interactions with other proteins in the cartilage extracellular matrix. Binding studies with recombinant mutated and wild-type G3 proteins showed loss of fibulin-1, fibulin-2, and tenascin-R interactions for the V2303M protein. Mass spectrometric analyses of aggrecan purified from patient cartilage verified that V2303M aggrecan is produced and present in the tissue. Our results provide a molecular mechanism for the etiology of familial osteochondritis dissecans and show the importance of the aggrecan C-type lectin interactions for cartilage function in vivo.
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