Evidence for altered synthesis of type II collagen in patients with osteoarthritis.

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Objective. To study 3 body fluids for changes in the levels of 5 biomarkers of cartilage metabolism during the early phases of experimental osteoarthritis (OA).Methods. Twenty skeletally mature mixed-breed canines underwent unilateral surgical transection of the anterior cruciate ligament. Samples of joint fluid, serum, and urine were obtained preoperatively and just before necropsy (3 weeks or 12 weeks postoperatively). Biomarkers included 2 markers of cartilage matrix synthesis/turnover (aggrecan 846 epitope and C-propeptide of type II collagen) and 3 markers of cartilage degradation (keratan sulfate proteoglycan epitope, the collagenase-generated cleavage epitope of type II collagen [Col2-3/4C long mono , or CIIC], and crosslinked peptides from the C-telopeptide domain of type II collagen [Col2CTx]). Significant changes in the levels of these biomarkers were determined by paired analyses.Results. Joint pathology was more severe in the 12-week group compared with the 3-week group. In joint fluid, due to limited volume, only Col2-3/4C long mono and Col2CTx were measured. Significant elevations in the levels of both of these markers were observed in experimental joints in both the 3-week group and the 12-week group. In serum, the level of aggrecan 846 epitope was elevated at both 3 weeks and 12 weeks, the level of Col2-3/4C long mono was elevated at 12 weeks, and the level of Col2CTx was elevated at both 3 weeks and 12 weeks. In urine, the level of Col2-3/4C long mono was elevated at 12 weeks after surgery.Conclusion. Levels of biomarkers of intact aggrecan proteoglycan (aggrecan 846 epitope) and type II collagen degradation (Col2-3/4C long mono and Col2CTx) were elevated early after unilateral stifle joint injury, suggesting that these markers are sensitive and specific for early cartilage changes associated with isolated joint injury in this established model of experimental OA.The early stages of osteoarthritis (OA) are difficult to diagnose. Joint structure and function are typically altered substantially before symptoms cause patients to seek medical care, that is, the osteoarthritic process begins long before OA presents as a clinical disease. The insidious onset and "silent" progression of primary OA not only obscure an early diagnosis, but also delay treatment that may help prevent further cartilage destruction and joint failure. Hence, diagnostic tests that can detect and monitor molecular events early in the pathogenesis of OA would be potentially very useful.For nearly a century, synovial fluid analysis has been important in the differential diagnosis of arthritis. Although synovial fluid analysis is useful in distinguishing between inflammatory, septic, and crystal-induced arthritis, its value in OA is limited. Similarly, routine blood and urine analyses can identify certain inflammatory arthritides and metabolic defects that cause joint pain and pathology but, as yet, reveal little about the OA process. No specific molecular markers of the OA process are currently available for clinical use, and the...

Section: Methodsmentioning

confidence: 99%

Section: Body Fluid Biomarkers In Early Experimental Oa 549mentioning

confidence: 99%

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confidence: 99%

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Analysis of cartilage biomarkers in the early phases of canine experimental osteoarthritis

Matyas

Atley

Ionescu

et al. 2004

141

124

“…Biomarkers have also been developed targeting de novo epitopes on type I and type II collagen generated following cleavage of the triple helix by collagenases (detected by the C2C and C1,2C assays) (18)(19)(20). Others target the 846 epitope on chondroitin sulfate side chains of aggrecan (21).…”

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confidence: 99%

Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis

Maksymowych¹,

Landewé²,

Conner‐Spady³

et al. 2007

154

100

Objective. In prospective studies, only baseline radiographic damage has been identified as an independent predictor of radiographic progression in ankylosing spondylitis (AS). Several biomarkers have been identified as independent predictors of radiographic progression in rheumatoid arthritis, however, and these may be of use in AS. This study was undertaken to analyze serologic biomarkers as predictors of radiographic progression in AS.Methods. We measured a panel of biomarkers reflecting cartilage turnover and osteoclasis. These biomarkers were cartilage oligomeric matrix protein, human cartilage gp-39 (YKL-40), type II collagen epitopes detected by the C2C and C1,2C degradation assays and the CPII synthesis assay, aggrecan 846 epitope, osteoprotegerin, and matrix metalloproteinase 3 (MMP-3). The analysis was performed in a cohort of AS patients from the Netherlands, Belgium, and France enrolled in a longitudinal study, the Outcome Assessments in Ankylosing Spondylitis International Study. We examined 2-year radiographic progression data scored using the modified Stoke AS Spine Score (mSASSS).Results. Complete data were available on 97 patients. Only the biomarkers YKL-40 and MMP-3 showed weak to moderate univariate correlation with 2-year progression. After adjustment for sex, age, disease duration, C-reactive protein level, and baseline mSASSS, only MMP-3 was significantly associated with 2-year progression (␤ ‫؍‬ 0.29, P ‫؍‬ 0.004). Logistic regression analysis revealed MMP-3 (cutoff 68 ng/ml; odds ratio 9.4 [95% confidence interval 1.6-56]) and baseline mSASSS (cutoff 10 mSASSS units; odds ratio 18.6 [95% confidence interval 2.5-138]) as the only independent predictors of 2-year progression (cutoff 3 mSASSS units; model R 2 ‫؍‬ 50%). MMP-3 was primarily contributory in patients who already had substantial baseline damage (>10 mSASSS units).Conclusion. These results indicate that MMP-3 is a significant independent predictor of radiographic progression in patients with AS, particularly in those with preexisting radiographic damage.Ankylosing spondylitis (AS) is characterized by the presence of inflammation in the spine and the development of ankylosis in the facet joints and intervertebral discs, which leads to immobility and functional impairment. The degree and rate of progression of radiographic changes can be reliably assessed using a validated scoring method, the modified Stoke AS Spine Score (mSASSS), which records structural changes in

“…The chondrocytes within the cartilage are essential to maintaining the integrity of the tissue. They respond to tissue damage by increasing proteoglycan and collagen synthesis in an attempt to repair the damage (11,12). If repair fails, damage will progress, leading to degeneration of the articular cartilage.…”

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confidence: 99%

Accumulation of advanced glycation end products as a molecular mechanism for aging as a risk factor in osteoarthritis

DeGroot¹,

Verzijl²,

Wijk

et al. 2004

182

114

Objective. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly. Its etiology is largely unknown, but age is the most prominent risk factor. The current study was designed to test whether accumulation of advanced glycation end products (AGEs), which are known to adversely affect cartilage turnover and mechanical properties, provides a molecular mechanism by which aging contributes to the development of OA.Methods. The hypothesis that elevated AGE levels predispose to the development of OA was tested in the canine anterior cruciate ligament transection (ACLT) model of experimental OA. Cartilage AGE levels were enhanced in young dogs by intraarticular injections of ribose. This mimics the accumulation of AGEs without the interference of other age-related changes. The severity of OA was then assessed 7 weeks after ACLT surgery in dogs with normal versus enhanced AGE levels.Results. Intraarticular injections of ribose enhanced cartilage AGE levels ϳ5-fold, which is similar to the normal increase that is observed in old dogs. ACLT surgery resulted in more-pronounced OA in dogs with enhanced AGE levels. This was observed as increased collagen damage and enhanced release of proteoglycans. The attempt to repair the matrix damage was impaired; proteoglycan synthesis and retention were decreased at enhanced AGE levels. Mankin grading of histology sections also revealed more-severe OA in animals with enhanced AGE levels.Conclusion. These findings demonstrate increased severity of OA at higher cartilage AGE levels and provide the first in vivo experimental evidence for a molecular mechanism by which aging may predispose to the development of OA.The population of Western society is aging rapidly. Consequently, age-related diseases will increase greatly over the coming decades and will have a great impact on the quality of life of the elderly. Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting the elderly and poses a significant public health problem (1). The most prominent feature of OA is the progressive destruction of articular cartilage, resulting in impaired joint motion, severe pain, and, ultimately, disability (2). As yet, the etiology of OA remains largely unknown. The incidence of OA increases with age: Ͼ50% of the population over 60 years of age is affected (3,4). Although age is identified as the main risk factor for the development of OA, the mechanism by which aging is involved remains unclear. Age-related changes in the articular cartilage are expected to play an important role in the susceptibility of cartilage to OA.Articular cartilage derives its mechanical properties from its extracellular matrix. This matrix is composed of type II collagen, which forms a 3-dimensional network that provides the cartilage with resistance to tensile forces (5).