Changes in serum cartilage marker levels indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation

Bleasel, J. F.; Poole, A R; Heinegård, Dick; Saxne, Tore; Holderbaum, Daniel; Ionescu, Mirela; Jones, Paul K.; Moskowitz, R. W.

doi:10.1002/1529-0131(199901)42:1<39::aid-anr5>3.0.co;2-y

Cited by 55 publications

(27 citation statements)

References 29 publications

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“…This may be explained by the fact that long duration of the disease is likely to result in more cartilage destruction with consequent release of aggrecan into the joint fluid which then appears in the serum. These findings are in agreement with that reported in some literatures [30,36,37]. However, Sharif et al [38] and Conrozier et al [35] disagreed with our findings and postulated that increased expression of these epitopes might reflect the response of the articular cartilage to insult requiring initiation of a high level.…”

Section: Discussionsupporting

confidence: 92%

“…These findings could be explained by the fact that clinical evaluation does not necessarily reflect cartilage changes as no close link between such parameters and the tissue process was to be expected [32,35,39,40]. These results disagree with those of Campion et al [41], Thonar et al [42] and Bleasel et al [30] who reported that aggrecan turnover correlated positively with the clinical signs of knee OA. Moreover, Sharif et al [38] found that COMP levels significantly correlated with activity and severity of knee OA.…”

Section: Discussionmentioning

confidence: 90%

“…This result suggests that aggrecan and COMP are locally produced in the joint and high synovial fluid of these biomarkers are associated with rapid cartilage turnover [14,23,30].…”

Section: Discussionmentioning

confidence: 94%

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Aggrecan and Cartilage Oligomeric Matrix Protein in Serum and Synovial Fluid of Patients with Knee Osteoarthritis

El-Arman

El-Fayoumi

El-Shal

et al. 2010

HSS Journal®: The Musculoskeletal Journal of Hospital for Speci

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Aggrecan and cartilage oligomeric matrix protein (COMP) which are important degradation products of articular cartilage may be promising diagnostic markers in serum and/or synovial fluid for diagnosis of knee osteoarthritis (OA). Our objective was to measure serum and synovial fluid levels of aggrecan and COMP in patients with OA of the knee joint to find out if they could be of diagnostic value in OA and if their levels correlate with the clinical and radiological manifestations of the disease. Sixty-six patients suffering from primary knee OA with effusion (26 males and 40 females) were studied. Twenty individuals (six males and 14 females) with recent traumatic knee effusion matched for age and sex were chosen to serve as a control group. All subjects had thorough clinical and radiological (X-ray and MRI) evaluation. Aggrecan and COMP in serum and synovial fluid were measured by ELISA. Serum and synovial fluid aggrecan and COMP levels were significantly higher than the control. Serum and synovial fluid aggrecan and COMP levels were positively correlated with age, body mass index, disease duration, plain X-ray and MRI scores. In OA, serum and synovial fluid aggrecan and COMP levels are elevated and represent useful markers in the diagnosis. Moreover, these elevated levels positively correlated with radiological joint damage but not with clinical disease parameters. These markers have the potential to be used for monitoring articular cartilage destruction and response to different therapeutic modalities.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 90%

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Aggrecan and Cartilage Oligomeric Matrix Protein in Serum and Synovial Fluid of Patients with Knee Osteoarthritis

El-Arman

El-Fayoumi

El-Shal

et al. 2010

HSS Journal®: The Musculoskeletal Journal of Hospital for Speci

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“…Over the last decade, investigators have explored several candidate markers that quantify macromolecules (or their fragments) that are specific to, or most prominent in, cartilage, including the proteoglycan aggrecan (1-3), type II collagen (4)(5)(6)(7)(8), and cartilage oligomeric matrix protein (9,10). The ability to measure such metabolites in joint fluid, serum, and urine holds promise for clinically useful ways of diagnosing, staging, and monitoring the progression and therapeutic response of joint tissues to injury and disease.…”

mentioning

confidence: 99%

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

Matyas

Atley

Ionescu

et al. 2004

Arthritis & Rheumatism

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141

124

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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...

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“…4,5 Functionally, COMP facilitates type II collagen fibril assembly, enhances chondrocyte attachment in vitro, and interacts with other ECM proteins, including type II and IX collagens, matrilin 3, and SPARC. [6][7][8][9][10][11][12] In contrast, mutations in COMP cause misfolding of the protein, preventing export from the chondrocyte and resulting in massive retention within the endoplasmic reticulum (ER). 10,[13][14][15] Although this finding has long been appreciated, there was little understanding of the pathologic molecular mechanisms, which are critical to develop mechanism-driven therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

et al. 2017

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Mutations in cartilage oligomeric matrix protein cause pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating pseudoachondroplasia and other human cartilage disorders. INTRODUCTIONTreatments of skeletal dysplasia/dwarfing conditions, including pseudoachondroplasia (PSACH), are few and fraught with problems because of the inaccessibility of chondrocytes within the cartilage matrix and the relative avascular nature of the cartilage environment. PSACH is clinically characterized by disproportionate short stature, rhizomelic shortening of the long bones, brachydactyly, and extreme joint laxity. 1,2 Joint pain in childhood and osteoarthritis (OA) in early adulthood are the most debilitating features of PSACH; only symptomatic treatments are available and have limited efficacy. 2,3 The diagnosis is made between 2-3 years of age when linear growth slows and a waddling gait develops. 1,2 Because the diagnosis, in most cases, is made post-natally, treatments aimed at resolving the pathology will have to be started immediately after diagnosis.PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric extracellular matrix (ECM) glycoprotein abundant in musculoskeletal tissues. 4,5 Functionally, COMP facilitates type II collagen fibril assembly, enhances chondrocyte attachment in vitro, and interacts with other ECM proteins, including type II and IX collagens, matrilin 3, and SPARC. [6][7][8][9][10][11][12] In contrast, mutations in COMP cause misfolding of the protein, preventing export from the chondrocyte and resulting in massive retention within the endoplasmic reticulum (ER). 10,[13][14][15] Although this finding has long been appreciated, there was little understanding of the pathologic molecular mechanisms, which are critical to develop mechanism-driven therapeutics. To circumvent this proble...

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Changes in serum cartilage marker levels indicate altered cartilage metabolism in families with the osteoarthritis-related type II collagen gene COL2A1 mutation

Cited by 55 publications

References 29 publications

Aggrecan and Cartilage Oligomeric Matrix Protein in Serum and Synovial Fluid of Patients with Knee Osteoarthritis

Aggrecan and Cartilage Oligomeric Matrix Protein in Serum and Synovial Fluid of Patients with Knee Osteoarthritis

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

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

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