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de Groot R, Folgado PB, Yamamoto K, Martin DR, Koch CD, Debruin D, Blagg S, Minns AF, Bhutada S, Ahnström J, Larkin J, Aspberg A, Önnerfjord P, Apte SS, Santamaria S. Cleavage of Cartilage Oligomeric Matrix Protein (COMP) by ADAMTS4 generates a neoepitope associated with osteoarthritis and other forms of degenerative joint disease. Matrix Biol 2025; 135:106-124. [PMID: 39672391 DOI: 10.1016/j.matbio.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/02/2024] [Accepted: 12/10/2024] [Indexed: 12/15/2024]
Abstract
Osteoarthritis (OA) is a highly prevalent joint disease, affecting millions of people worldwide and characterized by degradation of articular cartilage, subchondral bone remodeling and low-grade inflammation, leading to pain, stiffness and disability. Cartilage Oligomeric Matrix Protein (COMP) is a major structural component of cartilage and its degradation has been proposed as a marker of OA severity/progression. Several proteases cleave COMP in vitro, however, it is unclear which of these COMPase activities is prevalent in an osteoarthritic joint. Here, using purified recombinant proteins, we show that A Disintegrin And Metalloproteinase with Thrombospondin motifs 4 (ADAMTS4) is the most potent COMPase, followed by ADAMTS1. Using liquid chromatography-tandem mass spectrometry, we identified several novel cleavage sites in COMP resulting from ADAMTS4 and ADAMTS1 activity. Cleavage at S77-V78 disrupted the pentameric organization of COMP and generated a neopeptide previously identified in the synovial fluid of OA patients. Immunoblots with anti-QQS77 antibodies confirmed that ADAMTS4 efficiently cleaved this peptide bond. By analyzing five ADAMTS4 variants, we found that the C-terminal spacer domain is strictly necessary for COMPase activity and identified the specific residues involved in the interaction with COMP. An inhibitory anti-ADAMTS4 antibody significantly decreased generation of the COMP QQS77 neoepitope in human OA cartilage explants, implicating ADAMTS4 as a key protease in generating the QQS77 neopeptides in OA. Since another major ADAMTS4 substrate is aggrecan, the most abundant proteoglycan in cartilage, these findings highlight that, by cleaving both COMP and aggrecan, ADAMTS4 may play a crucial role in modulating the structural integrity of cartilage.
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Affiliation(s)
- Rens de Groot
- Institute of Cardiovascular Science, University College London, 51 Chenies Mews, London WC1E 6HX, United Kingdom.
| | - Patricia Badía Folgado
- Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom
| | - Kazuhiro Yamamoto
- Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, 6 West Derby Street, Liverpool L7 8TX, United Kingdom
| | - Daniel R Martin
- Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Christopher D Koch
- Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Danielle Debruin
- Department of Biochemical Sciences, School of Biosciences, Faculty of Health and Medical Sciences, Edward Jenner Building, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom
| | - Sophie Blagg
- Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom
| | - Alexander F Minns
- Department of Biochemical Sciences, School of Biosciences, Faculty of Health and Medical Sciences, Edward Jenner Building, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom
| | - Sumit Bhutada
- Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Josefin Ahnström
- Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom
| | - Jonathan Larkin
- SynOA Therapeutics, Philadelphia, PA, USA; Research Unit of Health Sciences and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Anders Aspberg
- Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Patrik Önnerfjord
- Rheumatology and Molecular Skeletal Biology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Suneel S Apte
- Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Salvatore Santamaria
- Department of Immunology and Inflammation, Imperial College London, Du Cane Road, London W12 0NN, United Kingdom; Department of Biochemical Sciences, School of Biosciences, Faculty of Health and Medical Sciences, Edward Jenner Building, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom.
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Deng M, Tang C, Yin L, Jiang Y, Huang Y, Feng Y, Chen C. Clinical and omics biomarkers in osteoarthritis diagnosis and treatment. J Orthop Translat 2025; 50:295-305. [PMID: 39911590 PMCID: PMC11795539 DOI: 10.1016/j.jot.2024.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 11/03/2024] [Accepted: 12/09/2024] [Indexed: 02/07/2025] Open
Abstract
Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts the quality of life for hundreds of millions, and is a major cause of disability. Despite this, diagnostic and therapeutic options for OA are still limited. With advances in molecular biology, an increasing number of OA biomarkers have been identified, which not only enhances our understanding of OA pathogenesis, but also offers new approaches for OA diagnosis and treatment. This review discussed the research progress on traditional OA biomarkers, and analyzed the application of various omics, including genomics, transcriptomics, proteomics, and metabolomics, in the diagnosis and treatment of OA. Furthermore, we explored how integrating multi-omics methods can reveal interactions among different biomolecules and their roles in the development of OA. This emerging interdisciplinary approach not only provides a more comprehensive understanding of the fundamental biological characteristics of OA, but also aids in identifying new integrated biomarkers, thereby allowing for more accurate predictions of disease progression and treatment responses. The identification and development of biomarkers offer new perspectives in understanding OA, enhancing the specificity and sensitivity of biological diagnostic markers, providing a basis for the design of targeted drugs, and ultimately advancing the development of precision diagnosis and treatment strategies in clinical OA. This study provides an overview of both commonly used and emerging biomarkers of OA which is beneficial for a more accurate, timely, effective clinical diagnosis and treatment for OA.
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Affiliation(s)
- Muhai Deng
- College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Cong Tang
- College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
| | - Li Yin
- Department of Orthopaedics, General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Yunsheng Jiang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yang Huang
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Wound Infection and Drug, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Yong Feng
- Department of Orthopedic Surgery, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, 400014, China
| | - Cheng Chen
- College of Medical Informatics, Chongqing Medical University, Chongqing, 400016, China
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Golightly YM, Renner JB, Helmick CG, Jordan JM, Nelson AE. Looking back on 30+ years of the Johnston County Osteoarthritis Project while looking forward with the Johnston County Health Study: A narrative review. Osteoarthritis Cartilage 2024; 32:430-438. [PMID: 38237761 DOI: 10.1016/j.joca.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 11/29/2023] [Accepted: 01/08/2024] [Indexed: 01/22/2024]
Abstract
Over the last 30 years, knowledge of the epidemiology of osteoarthritis (OA) has dramatically advanced, and Osteoarthritis and Cartilage has been on the forefront of disseminating research findings from large OA cohort studies, including the Johnston County OA Project (JoCoOA). The JoCoOA is a population-based, prospective longitudinal cohort that began roughly 30 years ago with a key focus on understanding prevalence, incidence, and progression of OA, as well as its risk factors, in a predominantly rural population of Black and White adults 45+ years old in a county in the southeastern United States. Selected OA results that will be discussed in this review include racial differences, lifetime risk, biomarkers, mortality, and OA risk factors. The new Johnston County Health Study will also be introduced. This new cohort study of OA and comorbid conditions builds upon current OA knowledge and JoCoOA infrastructure and is designed to reflect changes in demographics and urbanization in the county and the region.
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Affiliation(s)
- Yvonne M Golightly
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; College of Allied Health Professions, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Jordan B Renner
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Radiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | | | - Joanne M Jordan
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Amanda E Nelson
- Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Abou-Raya A, Rizk M, AbdelGhani E, AbdelMegid N. Identification of serum micro-RNAs of early knee osteoarthritis in a cohort of Egyptian patients. ALEXANDRIA JOURNAL OF MEDICINE 2023. [DOI: 10.1080/20905068.2022.2140987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Anna Abou-Raya
- Alexandria University, Faculty of Medicine, Internal Medicine, Alexandria, Egypt
| | - Mohamed Rizk
- Alexandria University, Faculty of Medicine, Clinical Pathology, Alexandria, Egypt
| | - Eman AbdelGhani
- Alexandria University, Faculty of Medicine, Internal Medicine, Alexandria, Egypt
| | - Nermen AbdelMegid
- Alexandria University, Faculty of Medicine, Internal Medicine, Alexandria, Egypt
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O'Sullivan O, Ladlow P, Steiner K, Hillman C, Stocks J, Bennett AN, Valdes AM, Kluzek S. Current status of catabolic, anabolic and inflammatory biomarkers associated with structural and symptomatic changes in the chronic phase of post-traumatic knee osteoarthritis- a systematic review. OSTEOARTHRITIS AND CARTILAGE OPEN 2023; 5:100412. [PMID: 37877037 PMCID: PMC10590857 DOI: 10.1016/j.ocarto.2023.100412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 09/26/2023] [Indexed: 10/26/2023] Open
Abstract
Post-traumatic OA (PTOA) can occur within 5 years after a significant injury and is a valuable paradigm for identifying biomarkers. This systematic review aims to summarise published literature in human studies on the associations of known serum and synovial fluid biomarkers at least a year from injury to structural, symptomatic changes and underlying PTOA processes. A systematic review was performed using PRISMA guidelines, prospectively registered on PROSPERO (CRD42022371838), for all 'wet' biomarkers a year or more post-injury in 18-45-year-old participants. Three independent reviewers screened search results, extracted data, and performed risk of bias assessments (Newcastle-Ottawa Scale). Study heterogeneity meant a narrative synthesis was undertaken, utilising SWiM guidelines. 952 studies were identified, 664 remaining after deduplication. Following first-round screening, 53 studies underwent second-round screening against pre-determined criteria. Eight studies, with 879 participants (49 % male), were included, measuring serum (n = 7), synovial fluid (SF, n = 6), or both (n = 5). The pooled participant mean age was 29.1 (±4). 51 biomarkers were studied (serum = 38, SF = 13), with no correlation between paired serum and SF samples. One serum biomarker, cartilage oligomeric matrix protein (COMP), and four SF biomarkers, interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF), and COMP, were measured in multiple studies. Associations were described between 11 biomarkers related to catabolism (n = 4), anabolism (n = 2), inflammation (n = 4) and non-coding RNA (n = 1), with OA imaging changes (X-ray and MRI), pain, quality of life and function. Widespread differences in study design and methodology prevented meta-analysis, and evidence was generally weak. A unified approach is required before widespread research and clinical biomarker use.
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Affiliation(s)
- Oliver O'Sullivan
- Academic Department of Military Rehabilitation (ADMR), Defence Medical Rehabilitation Centre (DMRC), Stanford Hall, Loughborough, UK
- Academic Unit of Injury, Recovery and Inflammation Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Peter Ladlow
- Academic Department of Military Rehabilitation (ADMR), Defence Medical Rehabilitation Centre (DMRC), Stanford Hall, Loughborough, UK
- Department of Health, University of Bath, Bath, UK
| | - Kat Steiner
- Bodleian Health Care Libraries, University of Oxford, Oxford, UK
| | - Charles Hillman
- Academic Unit of Injury, Recovery and Inflammation Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Joanne Stocks
- Academic Unit of Injury, Recovery and Inflammation Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
| | - Alexander N. Bennett
- Academic Department of Military Rehabilitation (ADMR), Defence Medical Rehabilitation Centre (DMRC), Stanford Hall, Loughborough, UK
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Ana M. Valdes
- Nottingham NIHR Biomedical Research Centre, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
- Department of Twin Research & Genetic Epidemiology, King's College London, London, UK
| | - Stefan Kluzek
- Academic Unit of Injury, Recovery and Inflammation Sciences, Faculty of Medicine and Health Sciences, University of Nottingham, Nottingham, UK
- Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, University of Nottingham, Nottingham, UK
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Papaneophytou C, Alabajos-Cea A, Viosca-Herrero E, Calvis C, Costa M, Christodoulides AE, Kroushovski A, Lapithis A, Lapithi VM, Papayiannis I, Christou A, Messeguer R, Giannaki C, Felekkis K. Associations between serum biomarkers of cartilage metabolism and serum hyaluronic acid, with risk factors, pain categories, and disease severity in knee osteoarthritis: a pilot study. BMC Musculoskelet Disord 2022; 23:195. [PMID: 35236298 PMCID: PMC8889762 DOI: 10.1186/s12891-022-05133-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 02/15/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Specific serum biomarkers of cartilage metabolism such as cartilage oligomeric matrix protein (sCOMP) and procollagen type II C-terminal propeptide (sPIICP) as well as hyaluronan (sHA), a biomarker of synovitis, have been implicated in the pathophysiology of knee osteoarthritis (OA). However, the associations of these biomarkers with the severity of the disease and OA risk factors, including age and obesity remain inconclusive. This analysis examines the associations between these serum biomarkers and the radiographic severity of OA and knee pain, as wells as obesity, the age and gender of the participants, and other OA risk factors. METHODS From 44 patients with early knee OA and 130 patients with late knee OA we analyzed the radiographic severity of the disease using the Kellgren and Lawrence (KL) grading system. Moreover, 38 overweight healthy individuals were used as a control group. Specific information was collected from all participants during their recruitment. The levels of the three serum biomarkers were quantified using commercially available ELISA kits. Serum biomarkers were analyzed for associations with the average KL scores and pain in both knees, as well as with specific OA risk factors. RESULTS The levels of sCOMP were elevated in patients with severe late OA and knee pain and correlated weakly with OA severity. A weakly correlation of sHA levels and OA severity OA was observed. We demonstrated that only sPIICP levels were markedly decreased in patients with late knee OA suggesting the alterations of cartilage metabolism in this arthritic disease. Moreover, we found that sPIICP has the strongest correlation with obesity and the severity of OA, as well as with the knee pain at rest and during walking regardless of the severity of the disease. ROC analysis showed that the area under the ROC curve (AUC) was 0.980 (95% CI: 0.945-0.995; p < 0.0001), suggesting high diagnostic accuracy of sPIICP. Interestingly, gender and age had also an effect on the levels of sPIICP. CONCLUSION This study revealed the potential of serum PIICP to be used as a biomarker to monitor the progression of knee OA, however, further studies are warranted to elucidate its clinical implication.
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Affiliation(s)
- Christos Papaneophytou
- Department of Life and Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417, Nicosia, Cyprus
| | - Ana Alabajos-Cea
- Physical Medicine & Rehabilitation Department, Hospital La Fe, 46026, Valencia, Spain
- Health Research Institute La Fe, 46026, Valencia, Spain
| | | | - Carme Calvis
- Drug Development Area, Health & Biomedicine Department, LEITAT Technological Centre, Parc Científic de Barcelona, 08028, Barcelona, Spain
| | - Marta Costa
- Drug Development Area, Health & Biomedicine Department, LEITAT Technological Centre, Parc Científic de Barcelona, 08028, Barcelona, Spain
| | | | - Alexander Kroushovski
- Apollonion Hospital, 2054, Nicosia, Cyprus
- Medical School, University of Nicosia, 2408, Nicosia, Cyprus
| | | | | | | | | | - Ramon Messeguer
- Drug Development Area, Health & Biomedicine Department, LEITAT Technological Centre, Parc Científic de Barcelona, 08028, Barcelona, Spain
| | - Christoforos Giannaki
- Department of Life and Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417, Nicosia, Cyprus.
| | - Kyriacos Felekkis
- Department of Life and Health Sciences, School of Sciences and Engineering, University of Nicosia, 2417, Nicosia, Cyprus.
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Hall M, van der Esch M, Hinman RS, Peat G, de Zwart A, Quicke JG, Runhaar J, Knoop J, van der Leeden M, de Rooij M, Meulenbelt I, Vliet Vlieland T, Lems WF, Holden MA, Foster NE, Bennell KL. How does hip osteoarthritis differ from knee osteoarthritis? Osteoarthritis Cartilage 2022; 30:32-41. [PMID: 34600121 DOI: 10.1016/j.joca.2021.09.010] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/01/2021] [Accepted: 09/21/2021] [Indexed: 02/02/2023]
Abstract
Hip and knee osteoarthritis (OA) are leading causes of global disability. Most research to date has focused on the knee, with results often extrapolated to the hip, and this extends to treatment recommendations in clinical guidelines. Extrapolating results from research on knee OA may limit our understanding of disease characteristics specific to hip OA, thereby constraining development and implementation of effective treatments. This review highlights differences between hip and knee OA with respect to prevalence, prognosis, epigenetics, pathophysiology, anatomical and biomechanical factors, clinical presentation, pain and non-surgical treatment recommendations and management.
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Affiliation(s)
- M Hall
- Centre for Health Exercise and Sports Medicine, Department of Physiotherapy, School of Health Sciences, The University of Melbourne, Australia
| | - M van der Esch
- Reade, Center for Rehabilitation and Rheumatology, Amsterdam, the Netherlands; Center of Expertise Urban Vitality, University of Applied Sciences Amsterdam, the Netherlands
| | - R S Hinman
- Centre for Health Exercise and Sports Medicine, Department of Physiotherapy, School of Health Sciences, The University of Melbourne, Australia
| | - G Peat
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, UK
| | - A de Zwart
- Reade, Center for Rehabilitation and Rheumatology, Amsterdam, the Netherlands
| | - J G Quicke
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, UK
| | - J Runhaar
- Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - J Knoop
- Vrije Universiteit Amsterdam, the Netherlands
| | - M van der Leeden
- Reade, Center for Rehabilitation and Rheumatology, Amsterdam, the Netherlands; Amsterdam UMC, Location VUmc, Department of Rheumatology, Amsterdam, the Netherlands
| | - M de Rooij
- Reade, Center for Rehabilitation and Rheumatology, Amsterdam, the Netherlands
| | | | | | - W F Lems
- Reade, Center for Rehabilitation and Rheumatology, Amsterdam, the Netherlands; Amsterdam UMC, Location VUmc, Department of Rheumatology, Amsterdam, the Netherlands
| | - M A Holden
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, UK
| | - N E Foster
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, UK; STARS Research and Education Alliance, Surgical Treatment and Rehabilitation Service (STARS), The University of Queensland and Metro North Hospital and Health Service, Queensland, Australia
| | - K L Bennell
- Centre for Health Exercise and Sports Medicine, Department of Physiotherapy, School of Health Sciences, The University of Melbourne, Australia.
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Liem Y, Judge A, Kirwan J, Ourradi K, Li Y, Sharif M. Multivariable logistic and linear regression models for identification of clinically useful biomarkers for osteoarthritis. Sci Rep 2020; 10:11328. [PMID: 32647218 PMCID: PMC7347626 DOI: 10.1038/s41598-020-68077-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 06/16/2020] [Indexed: 12/21/2022] Open
Abstract
Osteoarthritis (OA) is the most common chronic degenerative joint disease which causes substantial joint pain, deformity and loss of activities of daily living. Currently, there are over 500 million OA cases worldwide, and there is an urgent need to identify biomarkers for early detection, and monitoring disease progression in patients without obvious radiographic damage to the joint. We have used regression modelling to describe the association of 19 of the currently available biomarkers (predictors) with key radiographic and clinical features of OA (outcomes) in one of the largest and best characterised OA cohort (NIH Osteoarthritis Initiative). We demonstrate that of the 19 currently available biomarkers only 4 (serum Coll2-1 NO2, CS846, COMP and urinary CTXII) were consistently associated with established radiographic and/or clinical features of OA. These biomarkers are independent of one another and provide additional predictive power over, and above established predictors of OA such as age, gender, BMI and race. We also show that that urinary CTXII had the strongest and consistent associations with clinical symptoms of OA as well as radiographic evidence of joint damage. Accordingly, urinary CTXII may aid in early diagnosis of OA in symptomatic patients without radiographic evidence of OA.
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Affiliation(s)
- Yulia Liem
- Translational Health Sciences, Bristol Medical School, Musculoskeletal Research Unit, Southmead Hospital, University of Bristol, Learning and Research Building (Level 2), Bristol, BS10 5NB, UK
| | - Andrew Judge
- Translational Health Sciences, Bristol Medical School, Musculoskeletal Research Unit, Southmead Hospital, University of Bristol, Learning and Research Building (Level 2), Bristol, BS10 5NB, UK
| | - John Kirwan
- University of Bristol, Biomedical Sciences Building, University Walk, Bristol, UK
| | - Khadija Ourradi
- Translational Health Sciences, Bristol Medical School, Musculoskeletal Research Unit, Southmead Hospital, University of Bristol, Learning and Research Building (Level 2), Bristol, BS10 5NB, UK
| | - Yunfei Li
- Translational Health Sciences, Bristol Medical School, Musculoskeletal Research Unit, Southmead Hospital, University of Bristol, Learning and Research Building (Level 2), Bristol, BS10 5NB, UK
| | - Mohammed Sharif
- Translational Health Sciences, Bristol Medical School, Musculoskeletal Research Unit, Southmead Hospital, University of Bristol, Learning and Research Building (Level 2), Bristol, BS10 5NB, UK.
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Boeth H, Raffalt PC, MacMahon A, Poole AR, Eckstein F, Wirth W, Buttgereit F, Önnerfjord P, Lorenzo P, Klint C, Pramhed A, Duda GN. Association between changes in molecular biomarkers of cartilage matrix turnover and changes in knee articular cartilage: a longitudinal pilot study. J Exp Orthop 2019; 6:19. [PMID: 31053993 PMCID: PMC6499840 DOI: 10.1186/s40634-019-0179-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 03/07/2019] [Indexed: 12/26/2022] Open
Abstract
Background An early detection of Osteoarthritis is urgently needed and still not possible until today. The aim of the study was to assess whether molecular biomarkers of cartilage turnover are associated with longitudinal change in knee cartilage thickness during a 2 year period in individuals with increased risk of developing knee osteoarthritis. A secondary aim was to assess whether prior knee injury or subjective patient-reported outcomes at baseline (BL) were associated with articular cartilage changes. Nineteen volleyball players (mean age 46.5 ± 4.9 years, 47% male) with a 30-year history of regular high impact training were recruited. The serum biomarkers Cpropeptide of type II procollagen (CPII), cartilage oligomeric matrix protein (COMP), collagenase generated carboxy-terminal neoepitope of type II collagen (sC2C), cartilage intermediate layer protein 2 (CILP-2), and the urine biomarkers C-telopeptide of type II collagen (CTX-II) and collagenase-generated peptide(s) of type II collagen (C2C-HUSA) were assessed at BL and at 2 year follow up (FU). Femorotibial cartilage thinning, thickening and absolute thickness change between BL and FU was evaluated from magnetic resonance imaging. Subjective clinical status at BL was evaluated by the International Knee Documentation Committee Subjective Knee Form and the Short-Form 36 Physical Component Score. Results CILP-2 was significantly higher at FU and linearly associated with the absolute cartilage thickness change during the experimental period. Prior injury was a predictor of increased absolute cartilage thickness change. Conclusion Measuring the change in the cartilage biomarker CILP-2 might be a valid and sensitive method to detect early development of knee osteoarthritis as CILP-2 appears to be related to cartilage thickness loss in certain individuals with increased risk of developing knee osteoarthritis. Prior knee injury may be predictive of increased articular cartilage thickness change.
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Affiliation(s)
- Heide Boeth
- Julius Wolff Institute, Charité - Universitätsmedizin, Berlin, Germany
| | - Peter C Raffalt
- Julius Wolff Institute, Charité - Universitätsmedizin, Berlin, Germany
| | - Aoife MacMahon
- Julius Wolff Institute, Charité - Universitätsmedizin, Berlin, Germany
| | - A Robin Poole
- Department of Surgery, McGill University, Montreal, Quebec, Canada
| | - Felix Eckstein
- Institute of Anatomy, Paracelsus Medical University, Salzburg & Nuremberg, Salzburg, Austria
| | - Wolfgang Wirth
- Institute of Anatomy, Paracelsus Medical University, Salzburg & Nuremberg, Salzburg, Austria
| | - Frank Buttgereit
- Med. Klinik m. S. Rheumatologie und Klinische Immunologie, Charité - Universitätsmedizin, Berlin, Germany
| | | | - Pilar Lorenzo
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | | | | | - Georg N Duda
- Julius Wolff Institute, Charité - Universitätsmedizin, Berlin, Germany.
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10
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Cartilage oligomeric matrix protein, C-terminal cross-linking telopeptide of type II collagen, and matrix metalloproteinase-3 as biomarkers for knee and hip osteoarthritis (OA) diagnosis: a systematic review and meta-analysis. Osteoarthritis Cartilage 2019; 27:726-736. [PMID: 30391538 DOI: 10.1016/j.joca.2018.10.009] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/25/2018] [Accepted: 10/08/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study was design to examine the diagnostic performance of cartilage oligomeric matrix protein (COMP), C-terminal cross-linking telopeptide of type II collagen (CTX-II), and matrix metalloproteinase-3 (MMP-3) as biomarker for knee and hip OA. METHODS Systematic search on multiple databases was completed in January 2018 using certain keywords. COMP, CTX-II, MMP-3 levels in knee and hip OA patients and healthy individuals were collected and calculated. Differences between subgroups were expressed as standardized mean differences (SMD). Subgroup analyses were performed to compare COMP, CTX-II, and MMP-3 performance between measuring sources, genders, large and small sample size and diagnostic criteria for OA patients. RESULTS A moderate performance of COMP in distinguishing between knee (SMD: 0.68; 95% confidence intervals (CI): 0.43-0.93; P < 0.0001) or hip (SMD: 0.25; 95% CI, 0.10, 0.40; P = 0.0008) OA patients and controls were found. CTX-II showed a moderated standardised mean differences (SMD) of 0.48 (95% CI, 0.32, 0.64; P < 0.0001) in the detection of knee OA and a large SMD of 0.76 (95% CI, 0.09, 1.42; P = 0.03) in diagnosing hip OA. A small SMD of 0.32 (95% CI, -0.03, 0.67; P = 0.07) was found for MMP-3 performance and the results did not reach statistic significance. Progression study revealed potential effectiveness of serum COMP in predicting OA progression. Subgroup analysis showed that serum COMP and urinary CTX-II performed better in male than female. Study size and diagnostic criteria did not significantly influence the pooled SMD, but they might be the sources of heterogeneity among studies. CONCLUSION The overall results indicates that serum COMP and urinary CTX-II can distinguish between knee or hip OA patients and control subjects. Serum COMP is effective in predicting OA progression.Further researches with rigorous study design and a larger sample size are required to validate our findings.
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Laudon J, Whittaker JL, Ren G, Jaremko JL, Emery CA, Krawetz RJ. Serum cartilage oligomeric matrix protein (COMP) expression in individuals who sustained a youth sport-related intra-articular knee injury 3-10 years previously and uninjured matched controls. Osteoarthritis Cartilage 2019; 27:286-293. [PMID: 30317002 DOI: 10.1016/j.joca.2018.09.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 09/22/2018] [Accepted: 09/26/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study investigates the relationship between a youth sport-related intra-articular knee injury and cartilage oligomeric matrix protein (COMP), a biomarker of cartilage turnover. DESIGN Participants included a sub-sample (n = 170) of the Alberta Youth Prevention of Early Osteoarthritis (PrE-OA) study group. Specifically, 85 individuals with a 3-10 year history of sport-related intra-articular knee injury and 85 age, sex and sport-matched controls. COMP levels were investigated in serum. Between group differences in COMP levels, COMP fragmentation patterns and, the relationship between serum COMP and clinical outcomes (i.e., Magnetic Resonance Imaging (MRI) Osteoarthritis Knee Score; MOAKS, Knee Osteoarthritis Outcome Score; KOOS, Fat mass index; FMI) were examined. RESULTS Participant median age was 22.3 years (range 16-26) and 63% were female. Although there was no difference in COMP levels between previously injured and uninjured females, previously injured males demonstrated an ∼15% greater (171.5 ng/ml, 95% CI 11.0-428.0, P = 0.04) serum COMP level than uninjured males. However after controlling for FMI, this difference was absent. Within the injured participants, COMP levels were associated with MOAKSSYNOVITIS and FMI. Furthermore, COMP fragmentation patterns were distinct between injured and uninjured individuals. CONCLUSIONS In this study group, serum COMP levels were greater in injured males, but not females, compared to matched controls. However, after controlling for FMI, no differences in COMP were observed. A unique COMP fragmentation pattern was observed in injured vs uninjured participants. These results further the hypothesis that COMP levels and/or degradation of the protein may be a marker of cartilage injury which could predispose to later OA.
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Affiliation(s)
- J Laudon
- Faculty of Kinesiology, Sport Injury Prevention Research Centre, University of Calgary, Calgary, Alberta, Canada.
| | - J L Whittaker
- Faculty of Kinesiology, Sport Injury Prevention Research Centre, University of Calgary, Calgary, Alberta, Canada; Faculty of Rehabilitation Medicine, Department of Physical Therapy, University of Alberta, Edmonton, Alberta, Canada; Glen Sather Sports Medicine Clinic, University of Alberta, Edmonton, Alberta, Canada.
| | - G Ren
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada.
| | - J L Jaremko
- Department of Radiology and Diagnostic Imaging, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
| | - C A Emery
- Faculty of Kinesiology, Sport Injury Prevention Research Centre, University of Calgary, Calgary, Alberta, Canada; Department of Pediatrics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, Alberta, Canada.
| | - R J Krawetz
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, Alberta, Canada; McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, Alberta, Canada; Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; The D-BOARD European Consortium for Biomarker Discovery, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
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12
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Zhao ZJ, Li Q, Ma L, Li JQ, Xu LQ. The early diagnostic value of serum neopterin and cartilage oligomeric matrix protein for osteoarticular changes among brucellosis patients at an early period. J Orthop Surg Res 2018; 13:222. [PMID: 30180854 PMCID: PMC6123995 DOI: 10.1186/s13018-018-0932-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 08/24/2018] [Indexed: 01/09/2023] Open
Abstract
Background Brucellosis is an important public health problem in China. Brucellosis can cause many osteoarticular changes, especially chronic brucellosis. Brucellosis presents various diagnostic difficulties because it mimics many other diseases. Because of the poor sensitivity and ability of X-ray image, it is necessary to find a good method of early diagnosis for osteoarticular changes among brucellosis patients at an early period. The aim of this study was to find early changes biomarkers for osteoarticular changes among brucellosis patients at an early period and provide a better understanding of the osteoarticular changes in this disease at an early stage. Methods Sixty-one cases of brucellosis patients at an early period (within 6 months) and 67 cases of volunteers were selected and divided into brucellosis vs. control groups. Serum samples were detected with serological tests for brucellosis, including rose bengal plate test (RBPT), agglutination test (SAT), and IgG and IgM with ELISA. Meanwhile, cartilage oligomeric matrix protein (COMP) and neopterin (NPT) levels in all samples were measured simultaneously with ELISA. The data were analyzed using SPSS 17.0 software. Results Together with the clinical examination, epidemiological investigation, and serological tests of RBPT, SAT, and IgG and IgM with ELISA, the patients from brucellosis group all were diagnosed as brucellosis cases at an early period, while the results of RBPT, SAT, and IgG and IgM with ELISA from the healthy control group were negative. Comparing with the healthy control, the medians of serum NPT and COMP in the patients group were 9.26 ng/l, 1.70 ng, respectively, which were higher than that of the healthy control group with significant differences (Z = 5.512, 3.614, all p = 0.000). Conclusion The serum NPT and COMP levels of brucellosis patients at an early period were increased. The serum NPT and COMP levels might be the indicator biomarker for osteoarticular changes of human brucellosis at an early stage.
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Affiliation(s)
- Zhi-Jun Zhao
- Qinghai Institute for Endemic Disease Prevention and Control, Xining, 811602, Qinghai, China
| | - Qiang Li
- Qinghai Institute for Endemic Disease Prevention and Control, Xining, 811602, Qinghai, China
| | - Li Ma
- Qinghai Institute for Endemic Disease Prevention and Control, Xining, 811602, Qinghai, China
| | - Ji-Quan Li
- Qinghai Institute for Endemic Disease Prevention and Control, Xining, 811602, Qinghai, China
| | - Li-Qing Xu
- Qinghai Institute for Endemic Disease Prevention and Control, Xining, 811602, Qinghai, China.
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13
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Luyten FP, Bierma-Zeinstra S, Dell'Accio F, Kraus VB, Nakata K, Sekiya I, Arden NK, Lohmander LS. Toward classification criteria for early osteoarthritis of the knee. Semin Arthritis Rheum 2018; 47:457-463. [PMID: 28917712 DOI: 10.1016/j.semarthrit.2017.08.006] [Citation(s) in RCA: 118] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 07/24/2017] [Accepted: 08/04/2017] [Indexed: 01/06/2023]
Abstract
OBJECTIVE To propose draft classification criteria for early stage osteoarthritis (OA) of the knee for use in a primary care setting. METHODS A group of basic scientists, physician-scientists, rheumatologists, orthopedic surgeons, and physiotherapists in a workshop setting discussed potential classification criteria for early osteoarthritis of the knee. The workshop was divided into sessions around relevant topics with short state of the art presentations followed by breakout sessions, consensus discussions, and consolidation into a consensus document. RESULTS Three classes of criteria were agreed: (1) Pain, symptoms/signs, self-reported function, and quality of life using tools such as KOOS: scoring ≤85% in at least 2 out of these 4 categories; (2) Clinical examination: at least 1 present out of joint line tenderness or crepitus; (3) Knee radiographs: Kellgren & Lawrence (KL) grade of 0 or 1. MRI is at present not recommended as an aid to identify or define early OA in routine clinical practice or primary care, in light of the absence of validated consensus criteria and the high population prevalence of structural joint changes detected by this method. Biomarkers may have future utility in early OA classification, but no individual or set of biomarkers is yet robust enough. CONCLUSION Based on our consensus proposal, draft classification criteria for early OA of the knee for use in clinical studies should include patient reported outcomes such as pain and function, together with clinical signs and KL grade 0-1 on radiographs.
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Affiliation(s)
- F P Luyten
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Herestraat 49 Box 813, B-3000 Leuven, Belgium.
| | - S Bierma-Zeinstra
- Department of General Practice, University Medical Center Rotterdam, Erasmus MC, Rotterdam, the Netherlands; Department of Orthopedics, University Medical Center Rotterdam, Erasmus MC, Rotterdam, the Netherlands
| | - F Dell'Accio
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - V B Kraus
- Division of Rheumatology, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC
| | - K Nakata
- Medicine for Sports and Performing Arts, Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, Osaka, Japan
| | - I Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - N K Arden
- Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, University of Oxford, Oxford, England
| | - L S Lohmander
- Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden
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Suyasa IK, Kawiyana IKS, Bakta IM, Widiana IGR. Interleukin-6 and ratio of plasma interleukin-6/interleukin-10 as risk factors of symptomatic lumbar osteoarthritis. World J Orthop 2017; 8:149-155. [PMID: 28251065 PMCID: PMC5314144 DOI: 10.5312/wjo.v8.i2.149] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 11/18/2016] [Accepted: 12/09/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the role of cartilage oligomeric matrix protein (COMP), interleukin (IL)-6, IL-10 and ratio of IL-6/IL-10 as risk factors of symptomatic lumbar osteoarthritis (OA) in postmenopausal women with estrogen deficiency.
METHODS Case-control study had been conducted in Sanglah General Hospital from October 2015 until March 2016. The blood samples were obtained and analyzed by enzyme-linked immunosorbent assay (ELISA).
RESULTS From 44 pairs of samples which divided into 44 samples as case group and 44 samples as control group showed that high level of COMP in estrogen deficiency postmenopausal women were not at risk (OR = 0.7; 95%CI: 0.261-1.751; P = 0.393) for symptomatic lumbar OA (cut-off point 0.946). Estrogen deficiency in postmenopausal women with the high level of IL-6 had 2.7 times risk (OR = 2.7; 95%CI: 0.991-8.320; P = 0.033) for symptomatic lumbar OA from the low level of IL-6 (cut-off point 2.264). At lower level of IL-10, there was no risk for symptomatic lumbar OA (OR = 0.6; 95%CI: 0.209-1.798; P = 0.345) than with the higher level of IL-10 (cut-off point 6.049). While the high ratio of IL-6/IL-10 level in estrogen deficiency postmenopausal women gave 3.4 times risk (OR = 3.4; 95%CI: 1.204-11.787; P = 0.011) for symptomatic lumbar OA than the low ratio of IL-6/IL-10 level (cut-off point 0.364).
CONCLUSION High ratio of IL-6/IL-10 plasma level was the highest risk factor for causing symptomatic lumbar OA in postmenopausal women with estrogen deficiency.
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15
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Bertuglia A, Pagliara E, Grego E, Ricci A, Brkljaca-Bottegaro N. Pro-inflammatory cytokines and structural biomarkers are effective to categorize osteoarthritis phenotype and progression in Standardbred racehorses over five years of racing career. BMC Vet Res 2016; 12:246. [PMID: 27821120 PMCID: PMC5100096 DOI: 10.1186/s12917-016-0873-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 10/26/2016] [Indexed: 01/26/2023] Open
Abstract
Background Joint impact injuries initiate a progressive articular damage finally leading to post-traumatic osteoarthritis (PTOA). Racehorses represent an ideal, naturally available, animal model of the disease. Standardbred racehorses developing traumatic osteoarthritis of the fetlock joint during the first year of their career were enrolled in our study. Age-matched controls were contemporarily included. Biomarker levels of equine osteoarthritis were measured in serum and synovial fluid (SF) at baseline, and repeated yearly over the next 4 years of training (from T1 to T4). The effect of time and disease on the biomarker concentrations were analysed, and their relationship with clinical and radiographic parameters were assessed. We hypothesized that the kinetics of pro-inflammatory cytokines and structural biomarkers of joint disease would demonstrate progression of degenerative joint status during post-traumatic osteoarthritis and clarify the effect of early joint trauma. Results The concentrations of IL1-ß, IL-6, TNF-α in the SF of PTOA group peaked at T0, decreased at T1, and then progressively increased with time, reaching levels higher than those observed at baseline starting from T3. CTXII and COMP levels were similar in PTOA and control horses at baseline, and increased in serum and synovial fluid of PTOA horses starting from T2 (serum and synovial CTXII, and serum COMP) or T3 (synovial COMP). The percentual change of TNF-α in the SF of the affected joints independently contributed to explaining the radiological changes at T3 vs T2 and T4 vs T3. Conclusions Temporal changes of selected biomarkers in STBRs with an acute episode of traumatic fetlock OA demonstrated that long-term increased concentrations of inflammatory cytokines, type II collagen fragments and COMP, in the SF and serum, are related to PTOA. Based on the observed decrease in inflammatory merkers at T1, we hypothesize that the progression of PTOA could be effectively modulated by proper treatment strategies. Annual variations of synovial concentration of TNF-α can reliably predict radiographic progression of PTOA.
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Affiliation(s)
- Andrea Bertuglia
- Dipartimento di Scienze Veterinarie, Università di Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Italy.
| | - Eleonora Pagliara
- Dipartimento di Scienze Veterinarie, Università di Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Italy
| | - Elena Grego
- Dipartimento di Scienze Veterinarie, Università di Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Italy
| | - Alessandro Ricci
- Dipartimento di Scienze Veterinarie, Università di Torino, Largo Paolo Braccini 2, 10095, Grugliasco, Italy
| | - Nika Brkljaca-Bottegaro
- Clinic for surgery, orthopaedics and ophthalmology, Faculty of Veterinary medicine, University of Zagreb, Heinzelova 55, 10000, Zagreb, Croatia
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Anwander H, Melkus G, Rakhra KS, Beaulé PE. T1ρ MRI detects cartilage damage in asymptomatic individuals with a cam deformity. J Orthop Res 2016; 34:1004-9. [PMID: 26573964 DOI: 10.1002/jor.23101] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 11/03/2015] [Indexed: 02/04/2023]
Abstract
Hips with a cam deformity are at risk for early cartilage degeneration, mainly in the anterolateral region of the joint. T1ρ MRI is a described technique for assessment of proteoglycan content in hyaline cartilage and subsequently early cartilage damage. In this study, 1.5 Tesla T1ρ MRI was performed on 20 asymptomatic hips with a cam deformity and compared to 16 healthy control hips. Cam deformity was defined as an alpha angle at 1:30 o'clock position over 60° and/or at 3:00 o'clock position over 50.5°. Hip cartilage was segmented and divided into four regions of interest (ROIs): anterolateral, anteromedial, posterolateral, and posteromedial quadrants. Mean T1ρ value of the entire weight bearing cartilage in hips with a cam deformity (34.0 ± 4.6 ms) was significantly higher compared to control hips (31.3 ± 3.2 ms, p = 0.050). This difference reached significance in the anterolateral (p = 0.042) and posteromedial quadrants (p = 0.041). No significant correlation between the alpha angle and T1ρ values was detected. The results indicate cartilage damage occurs in hips with a cam deformity before symptoms occur. A significant difference in T1ρ values was found in the anterolateral quadrant, the area of direct engagement of the deformity, and in the posteromedial quadrant. To conclude, T1ρ MRI can detect early chondral damage in asymptomatic hips with a cam deformity. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1004-1009, 2016.
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Affiliation(s)
- Helen Anwander
- Division of Orthopaedic Surgery, The Ottawa Hospital, Ottawa, Canada
| | - Gerd Melkus
- Department of Medical Imaging, The Ottawa Hospital, Ottawa, Canada.,Department of Radiology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Kawan S Rakhra
- Department of Medical Imaging, The Ottawa Hospital, Ottawa, Canada.,Department of Radiology, Faculty of Medicine, University of Ottawa, Ottawa, Canada
| | - Paul E Beaulé
- Division of Orthopaedic Surgery, The Ottawa Hospital, Ottawa, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Canada
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Kuhns BD, Weber AE, Levy DM, Wuerz TH. The Natural History of Femoroacetabular Impingement. Front Surg 2015; 2:58. [PMID: 26636088 PMCID: PMC4644807 DOI: 10.3389/fsurg.2015.00058] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 10/29/2015] [Indexed: 11/13/2022] Open
Abstract
Femoroacetabular impingement (FAI) is a clinical syndrome resulting from abnormal hip joint morphology and is a common cause of hip pain in young adults. FAI has been posited as a precursor to hip osteoarthritis (OA); however, conflicting evidence exists and the true natural history of the disease is unclear. The purpose of this article is to review the current understanding of how FAI damages the hip joint by highlighting its pathomechanics and etiology. We then review the current evidence relating FAI to OA. Lastly, we will discuss the potential of hip preservation surgery to alter the natural history of FAI, reduce the risk of developing OA and the need for future arthroplasty.
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Affiliation(s)
- Benjamin D Kuhns
- Department of Orthopedic Surgery, Division of Sports Medicine, Hip Preservation Center, Rush University Medical Center , Chicago, IL , USA
| | - Alexander E Weber
- Department of Orthopedic Surgery, Division of Sports Medicine, Hip Preservation Center, Rush University Medical Center , Chicago, IL , USA
| | - David M Levy
- Department of Orthopedic Surgery, Division of Sports Medicine, Hip Preservation Center, Rush University Medical Center , Chicago, IL , USA
| | - Thomas H Wuerz
- Division of Sports Medicine, Center for Hip Preservation, New England Baptist Hospital , Boston, MA , USA
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18
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Nepple JJ, Thomason KM, An TW, Harris-Hayes M, Clohisy JC. What is the utility of biomarkers for assessing the pathophysiology of hip osteoarthritis? A systematic review. Clin Orthop Relat Res 2015; 473:1683-701. [PMID: 25623593 PMCID: PMC4385333 DOI: 10.1007/s11999-015-4148-6] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Innovations in biologics offer great promise in the treatment of patients with orthopaedic conditions and in advancing our ability to monitor underlying disease pathophysiology. Our understanding of the pathophysiology of hip osteoarthritis (OA) has improved significantly in the last decade. Femoroacetabular impingement (FAI) and hip dysplasia are increasingly recognized and treated as forms of prearthritic hip disease, yet the inability of radiographic and MR imaging to identify patients before the onset of irreversible articular cartilage injury limits their use for early diagnosis and treatment of patients with these conditions. Molecular biomarkers, as objectively measureable indicators of the pathophysiology of hip OA, have the potential to improve diagnosis, disease staging, and prognosis of hip OA and prearthritic hip disease. Although research into molecular biomarkers of hip OA has been conducted, investigations in prearthritic hip disease have only recently begun. QUESTIONS/PURPOSES The purpose of our review was to assess the use of molecular biomarkers in the pathophysiology of hip OA, including (1) diagnosis; (2) disease staging; and (3) prognosis. We additionally aimed to summarize the available literature investigating the use of biomarkers in (4) prearthritic hip disease, including FAI and hip dysplasia. METHODS We conducted a systematic review of molecular biomarkers associated with hip OA or prearthritic hip disease by searching four major electronic databases for keywords "hip", "osteoarthritis", "biomarker", and all synonyms. The search terms "femoroacetabular impingement" and "hip dysplasia" were also included. The biologic source of biomarkers was limited to serum, plasma, urine, and synovial fluid. The literature search yielded a total of 2740 results. Forty studies met all criteria and were included in our review. Studies were categorized regarding their relevance to (1) diagnosis; (2) disease staging; (3) prognosis; and/or (4) prearthritic hip disease. RESULTS Biomarker studies were characterized as relevant to diagnosis (16 studies), disease staging (15 studies), prognosis (11 studies), and prearthritic hip disease (three studies). Sixteen different biomarkers demonstrated associations relevant to the diagnosis of hip OA, 16 biomarkers demonstrated similar associations for disease staging, and six for prognosis. Six biomarkers seemed to be the most promising, demonstrating associations with hip OA in multiple studies, including: urinary level of type II collagen telopeptide (n = 5 studies), serum cartilage oligomeric protein (n = 4 studies), and serum C-reactive protein (n = 4 studies). Only three studies investigated the role of biomarkers in prearthritic hip disease, including two in FAI and one in unspecified etiology of pain. There were no studies about biomarkers in hip dysplasia. CONCLUSIONS Molecular biomarkers are increasingly investigated for their use in evaluating the pathophysiology of hip OA, but less so for prearthritic hip disease. Several biomarkers have demonstrated significant associations with hip OA across multiple studies. Further validation of these biomarkers is needed to assess their clinical use and potential application to prearthritic hip disease.
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Affiliation(s)
- Jeffrey J Nepple
- Department of Orthopaedic Surgery, Washington University School of Medicine, One Children's Place, Campus Box 8233, 4S60, St Louis, MO, 63110, USA,
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Kraus VB. Preclinical osteoarthritis. Rheumatology (Oxford) 2015. [DOI: 10.1016/b978-0-323-09138-1.00179-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Siebuhr AS, He Y, Gudmann NS, Gram A, Kjelgaard-Petersen CF, Qvist P, Karsdal MA, Bay-Jensen AC. Biomarkers of cartilage and surrounding joint tissue. Biomark Med 2014; 8:713-31. [DOI: 10.2217/bmm.13.144] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The identification and clinical demonstration of efficacy and safety of osteo- and chondro-protective drugs are met with certain difficulties. During the last few decades, the pharmaceutical industry has, in the field of rheumatology, experienced disappointments associated with the development of disease modification. Today, the vast amount of patients suffering from serious, chronic joint diseases can only be offered treatments aimed at improving symptoms, such as pain and acute inflammation, and are not aimed at protecting the joint tissue. This huge, unmet medical need has been the driver behind the development of improved analytical techniques allowing better and more efficient clinical trial design, implementation and analysis. With this review, we aim to provide a brief and general overview of biochemical markers of joint tissue, with special focus on neoepitopes. Furthermore, we highlight recent studies applying biochemical markers in joint degenerative diseases. These disorders, including osteoarthritis, rheumatoid arthritis and spondyloarthropathies, are the most predominant disorders in Europe and the USA, and have enormous socioeconomical impact.
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Affiliation(s)
- Anne S Siebuhr
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
| | - Yi He
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
| | - Natasja S Gudmann
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
| | - Aurelie Gram
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
| | | | - Per Qvist
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
| | - Morten A Karsdal
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
| | - Anne C Bay-Jensen
- Nordic Bioscience, Biomarkers & Research, Herlev Hovedgade 207, Herlev DK-2730, Denmark
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Nakajima S, Naruto T, Miyamae T, Imagawa T, Mori M, Nishimaki S, Yokota S. Improvement of reduced serum cartilage oligomeric matrix protein levels in systemic juvenile idiopathic arthritis patients treated with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol 2014. [DOI: 10.3109/s10165-008-0115-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Mobasheri A. Osteoarthritis year 2012 in review: biomarkers. Osteoarthritis Cartilage 2012; 20:1451-64. [PMID: 22842200 DOI: 10.1016/j.joca.2012.07.009] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 07/02/2012] [Accepted: 07/17/2012] [Indexed: 02/02/2023]
Abstract
PURPOSE Biomarkers provide useful diagnostic information by detecting cartilage degradation in osteoarthritis (OA), reflecting disease-relevant biological activity and predicting the course of disease progression. They also serve as surrogate endpoints in the drug discovery process. The aim of this narrative review was to focus on OA biomarker-related papers published between the osteoarthritis research society international (OARSI) 2011 meeting in San Diego and the OARSI 2012 meeting in Barcelona. METHODS The PubMed/MEDLINE and SciVerse Scopus bibliographic databases were searched using the keywords: 'biomarker' and 'osteoarthritis' and/or 'biomarker' and 'proteomics'. RESULTS Ninety-eight papers were found with the keywords 'biomarker' and 'osteoarthritis'. Fifteen papers were found with the keywords 'biomarker' and 'proteomics'. Review articles were also included. The most relevant published studies focused on extracellular matrix (ECM) molecules in body fluids. Enrichment of the deamidated epitope of cartilage oligomeric matrix protein (D-COMP) suggests that OA disease progression is associated with post-translational modifications that may show specificity for particular joint sites. Fibulin-3 peptides (Fib3-1 and Fib3-2) have been proposed as potential biomarkers of OA along with follistatin-like protein 1 (FSTL1), a new serum biomarker with the capacity to reflect the severity of joint damage. The 'membrane attack complex' (MAC) component of complement has also been implicated in OA. CONCLUSION Novel OA biomarkers are needed for sub-clinical disease diagnosis. Proteomic techniques are beginning to yield useful data and deliver new OA biomarkers in serum and urine. Combining biochemical markers with tissue and cell imaging techniques and bioinformatics (i.e., machine learning, clustering, data visualization) may facilitate the development of biomarker combinations enabling earlier detection of OA.
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Affiliation(s)
- A Mobasheri
- Musculoskeletal Research Group, School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, UK.
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Goode AP, Marshall SW, Kraus VB, Renner JB, Stürmer T, Carey TS, Irwin DE, Jordan JM. Association between serum and urine biomarkers and lumbar spine individual radiographic features: the Johnston County Osteoarthritis Project. Osteoarthritis Cartilage 2012; 20:1286-93. [PMID: 22890183 PMCID: PMC3608522 DOI: 10.1016/j.joca.2012.08.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Revised: 07/27/2012] [Accepted: 08/06/2012] [Indexed: 02/02/2023]
Abstract
OBJECTIVE (1) To determine associations between radiographic features of lumbosacral (LS) spine disc space narrowing (DSN) and osteophytes (OST) and joint metabolism biomarkers (serum cartilage oligomeric matrix protein (COMP), hyaluronic acid (HA), collagen neoepitope (C2C), C-propeptide of type II procollagen (CP-II), urine C-terminal cross-linking telopeptide (CTX-II) and N-terminal telopeptide (NTX-I)). (2) To explore interactions with race, gender and low back symptoms. DESIGN Cross-sectional analysis of 547 participants enrolled in the Johnston County (JoCo) Osteoarthritis Project from 2003 to 2004. Mean biomarker levels were estimated with linear regression. Proportional and partial-proportional odds models were used to estimate associations. Interactions were tested with likelihood ratio tests at a P-value < 0.10. Biomarkers were natural log (ln) transformed. RESULTS Significant differences in mean biomarker levels were found across severity of DSN for lnHA and lnC2C and lnCTX-II across severity of both DSN and OST. Moderate-to-strong associations were found between biomarkers of type II collagen and DSN, whereas associations with OST were weak. An association between lnHA and DSN was seen in women (adjusted odds ratio [aOR] = 1.34 (95% confidence intervals (CI) 1.08, 1.65)) but no association among men (aOR = 0.90 (95% CI 0.63, 1.26)). In Caucasians there was a decreased association with NTX-I and OST (aOR = 0.67 (95% CI 0.49, 0.91)) and no association in African Americans (AAs) (aOR = 1.06 (95% CI 0.76, 1.47)). There was a positive association of lnCOMP with DSN among those with low back symptoms (aOR = 1.82 (95% CI 1.02, 3.27)), but no association in those without low back symptoms (aOR = 0.65 (95% CI 0.35, 1.20)). CONCLUSION Joint metabolism biomarkers suggest biological differences in the pathologic process involved in DSN and OST that may be gender (HA) and ethnicity (NTX-I) specific.
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Affiliation(s)
- Adam P. Goode
- Department of Community and Family Medicine, Duke University Medical Center
| | - Stephen W. Marshall
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina
| | | | | | - Til Stürmer
- Department of Epidemiology, University of North Carolina
| | | | - Debra E. Irwin
- Department of Epidemiology, University of North Carolina
| | - Joanne M. Jordan
- Department of Medicine, Orthopedics, and Epidemiology, Division of Rheumatology, Allergy and Immunology, University of North Carolina
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Rousseau JC, Garnero P. Biological markers in osteoarthritis. Bone 2012; 51:265-77. [PMID: 22538364 DOI: 10.1016/j.bone.2012.04.001] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2011] [Revised: 03/07/2012] [Accepted: 04/03/2012] [Indexed: 12/01/2022]
Abstract
Osteoarthritis (OA) is considered as a chronic disease with a long "silent" period. The diagnosis is generally based on clinical symptoms and radiographic changes. However X-ray has a poor sensitivity and a relatively large precision error that does not allow an early detection of OA or the monitoring of joint damage progression. The limitations of the tools that are currently available for OA assessment have been the impetus to identify specific biological markers that reflect quantitative and dynamic variations in joint remodeling. Research has focused on the structural components of cartilage matrix, especially type II collagen degradation markers. In spite of a significant increase of some markers in individuals with early stage of OA, the large overlap with control subjects indicates that the current biomarkers used alone have limited diagnostic potential. However, the combination of specific markers seems to improve the prediction of disease progression at the individual level. Several types of treatment have been investigated but the lack of medications with definitively demonstrated chondroprotective activity has limited the assessment of the potential role of biomarkers for monitoring patients' responses to the treatment of OA. In this review, we will use the BIPED classification that appeared in 2006 for OA markers to describe the potential usage of a given marker [5]. This article is part of a Special Issue entitled "Osteoarthritis".
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Affiliation(s)
- J Ch Rousseau
- INSERM Unit 1033; Pathophysiology, Diagnosis and Treatments of bone diseases, Université de Lyon, Lyon, France.
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25
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Catterall JB, Hsueh MF, Stabler TV, McCudden CR, Bolognesi M, Zura R, Jordan JM, Renner JB, Feng S, Kraus VB. Protein modification by deamidation indicates variations in joint extracellular matrix turnover. J Biol Chem 2012; 287:4640-51. [PMID: 22179616 PMCID: PMC3281605 DOI: 10.1074/jbc.m111.249649] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Revised: 11/25/2011] [Indexed: 11/06/2022] Open
Abstract
As extracellular proteins age, they undergo and accumulate nonenzymatic post-translational modifications that cannot be repaired. We hypothesized that these could be used to systemically monitor loss of extracellular matrix due to chronic arthritic diseases such as osteoarthritis (OA). To test this, we predicted sites of deamidation in cartilage oligomeric matrix protein (COMP) and confirmed, by mass spectroscopy, the presence of deamidated (Asp(64)) and native (Asn(64)) COMP epitopes (mean 0.95% deamidated COMP (D-COMP) relative to native COMP) in cartilage. An Asp(64), D-COMP-specific ELISA was developed using a newly created monoclonal antibody 6-1A12. In a joint replacement study, serum D-COMP (p = 0.017), but not total COMP (p = 0.5), declined significantly after replacement demonstrating a joint tissue source for D-COMP. In analyses of 450 participants from the Johnston County Osteoarthritis Project controlled for age, gender, and race, D-COMP was associated with radiographic hip (p < 0.0001) but not knee (p = 0.95) OA severity. In contrast, total COMP was associated with radiographic knee (p < 0.0001) but not hip (p = 0.47) OA severity. D-COMP was higher in soluble proteins extracted from hip cartilage proximal to OA lesions compared with remote from lesions (p = 0.007) or lesional and remote OA knee (p < 0.01) cartilage. Total COMP in cartilage did not vary by joint site or proximity to the lesion. This study demonstrates the presence of D-COMP in articular cartilage and the systemic circulation, and to our knowledge, it is the first biomarker to show specificity for a particular joint site. We believe that enrichment of deamidated epitope in hip OA cartilage indicates a lesser repair response of hip OA compared with knee OA cartilage.
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MESH Headings
- Aged
- Aged, 80 and over
- Antibodies, Monoclonal, Murine-Derived/chemistry
- Arthroplasty, Replacement, Hip
- Arthroplasty, Replacement, Knee
- Asparagine/metabolism
- Aspartic Acid/metabolism
- Cartilage/metabolism
- Cartilage/pathology
- Cartilage/surgery
- Cartilage Oligomeric Matrix Protein
- Cohort Studies
- Enzyme-Linked Immunosorbent Assay
- Extracellular Matrix Proteins/metabolism
- Female
- Glycoproteins/metabolism
- Humans
- Male
- Mass Spectrometry
- Matrilin Proteins
- Middle Aged
- Osteoarthritis, Hip/metabolism
- Osteoarthritis, Hip/pathology
- Osteoarthritis, Hip/surgery
- Osteoarthritis, Knee/metabolism
- Osteoarthritis, Knee/pathology
- Osteoarthritis, Knee/surgery
- Protein Processing, Post-Translational
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Affiliation(s)
| | | | | | | | | | | | - Joanne M. Jordan
- the Thurston Arthritis Research Center and
- Departments of Medicine
- Orthopaedics, and
| | - Jordan B. Renner
- the Thurston Arthritis Research Center and
- Radiology, University of North Carolina, Chapel Hill, North Carolina 27514
| | - Sheng Feng
- Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710 and
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Seo SK, Yang HI, Lim KJ, Jeon YE, Choi YS, Cho S, Lee BS. Changes in Serum Levels of Cartilage Oligomeric Matrix Protein after Estrogen and Alendronate Therapy in Postmenopausal Women. Gynecol Obstet Invest 2012; 74:143-50. [DOI: 10.1159/000339934] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2011] [Accepted: 06/03/2012] [Indexed: 11/19/2022]
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Hoch JM, Mattacola CG, Medina McKeon JM, Howard JS, Lattermann C. Serum cartilage oligomeric matrix protein (sCOMP) is elevated in patients with knee osteoarthritis: a systematic review and meta-analysis. Osteoarthritis Cartilage 2011; 19:1396-404. [PMID: 22001901 PMCID: PMC3962955 DOI: 10.1016/j.joca.2011.09.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Revised: 09/15/2011] [Accepted: 09/23/2011] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To be used in diagnostic studies, it must be demonstrated that biomarkers can differentiate between diseased and non-diseased patients. Therefore, the purpose of this study was to answer the following questions: (1) Is serum cartilage oligomeric matrix protein (sCOMP) elevated in patients with radiographically diagnosed knee osteoarthritis (OA) compared to controls? (2) Are there differences in sCOMP levels when comparing differing radiographic OA severities to controls? METHODS Systematic review and meta-analysis. DATA SOURCES A systematic search of CINAHL, PEDro, Medline, and SportsDiscus was completed in March 2010. KEYWORDS knee, osteoarthritis, sCOMP, radiography. Study inclusion criteria: Studies were written in English, compared healthy adults with knee OA patients, used the Kellgren Lawrence (K/L) classification, measured sCOMP, and reported means and standard deviations for sCOMP. RESULTS For question 1, seven studies were included resulting in seven comparisons. A moderate overall effect size (ES) indicated sCOMP was consistently elevated in those with radiographically diagnosed knee OA when compared to controls (ES = 0.60, P < 0.001). For question 2, four studies were included resulting in 13 comparisons between radiographic OA severity levels and controls. Strong ESs were calculated for K/L-1 (ES = 1.43, P = 0.28), K/L-3 (ES = 1.05, P = 0.04), and K/L-4 (ES = 1.40, P = 0.003). A moderate ES was calculated for K/L-2 (ES = 0.60, P = 0.01). CONCLUSIONS These results indicate sCOMP is elevated in patients with knee OA and is sensitive to OA disease progression. Future research studies with a higher level of evidence should be conducted to investigate the use of this biomarker as an indicator for OA development and progression.
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Affiliation(s)
- J M Hoch
- Division of Athletic Training & Rehabilitation Sciences Doctoral Program, University of Kentucky, College of Health Sciences, 214 Wethington Building, 900 South Limestone, Lexington, KY 40536-0200, United States.
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Golightly YM, Marshall SW, Kraus VB, Renner JB, Villaveces A, Casteel C, Jordan JM. Biomarkers of incident radiographic knee osteoarthritis: do they vary by chronic knee symptoms? ARTHRITIS AND RHEUMATISM 2011; 63:2276-83. [PMID: 21506100 PMCID: PMC3149729 DOI: 10.1002/art.30412] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To explore the ability of osteoarthritis (OA)-related biomarkers to predict incident radiographic knee OA in a large sample of African American and Caucasian men and women. METHODS Baseline levels of serum cartilage oligomeric matrix protein (COMP), hyaluronan (HA), high-sensitivity C-reactive protein (hsCRP), and keratan sulfate (KS) and baseline and followup radiographs were available for 353 knees without baseline osteophyte formation and for 446 knees without baseline joint space narrowing (JSN). Cox models estimated the hazard ratio (HR) and 95% confidence interval (95% CI) for incident knee OA for a 1-unit increase in the ln of each biomarker, with adjustment for age, race, sex, body mass index, and knee OA of the contralateral limb. Report of chronic knee symptoms was explored as a modifier of the association. RESULTS The hazard of incident knee osteophytes (HR 2.16 [95% CI 1.39-3.37]) and incident JSN (HR 1.82 [95% CI 1.15-2.89]) increased with higher baseline ln(COMP) levels. The hazard of incident knee JSN increased with higher ln(HA) levels (HR 1.46 [95% CI 1.14-1.87]). Baseline ln(hsCRP) and ln(KS) did not predict incident knee outcomes. HRs per unit increase in ln(COMP), ln(HA), and ln(KS) were higher among knees with chronic symptoms than among those without symptoms. CONCLUSION Higher baseline ln(COMP) and ln(HA) levels were associated with incident knee OA over an average followup period of 6.3 years. These results represent detection of a molecular stage of OA prior to radiographic manifestations. Further exploration is needed to determine how chronic knee symptoms modify the biomarker-incident knee OA association.
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Affiliation(s)
- Yvonne M Golightly
- Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599-7280, USA.
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29
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El-Arman MM, El-Fayoumi G, El-Shal E, El-Boghdady I, El-Ghaweet A. Aggrecan and cartilage oligomeric matrix protein in serum and synovial fluid of patients with knee osteoarthritis. HSS J 2010; 6:171-6. [PMID: 21886532 PMCID: PMC2926364 DOI: 10.1007/s11420-010-9157-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2009] [Accepted: 01/29/2010] [Indexed: 02/07/2023]
Abstract
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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Affiliation(s)
| | - Ghada El-Fayoumi
- Department of Rheumatology and Rehabilitation, Mansoura University, Mansoura, Egypt
| | - ElWaleid El-Shal
- Department of Rheumatology and Rehabilitation, Mansoura University, Mansoura, Egypt
| | - Ibrahim El-Boghdady
- Department of Rheumatology and Rehabilitation, Mansoura University, Mansoura, Egypt
| | - Atef El-Ghaweet
- Department of Rheumatology and Rehabilitation, Mansoura University, Mansoura, Egypt
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Farouk HM, Mostafa AAA, Youssef SS, Elbeblawy MMS, Assaf NY, Elokda ESE. Value of entheseal ultrasonography and serum cartilage oligomeric matrix protein in the preclinical diagnosis of psoriatic arthritis. CLINICAL MEDICINE INSIGHTS-ARTHRITIS AND MUSCULOSKELETAL DISORDERS 2010; 3:7-14. [PMID: 21124691 PMCID: PMC2989640 DOI: 10.4137/cmamd.s4461] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Objective: To evaluate the utility of entheseal ultrasonography and serum COMP in the preclinical diagnosis of psoriatic arthritis. Methods: 60 psoriatic patients were divided into: 30 patients with psoriasis (group I) and 30 patients with psoriatic arthritis as control (group II). They underwent independent clinical and ultrasonographic examination of both lower limbs at the calcaneal insertions of Achilles tendons. Psoriatic arthritis disease activity and severity was assessed by modified DAS28 and Steinbrockers scores. Serum levels of COMP were measured for all patients by ELISA. Results: On clinical examination, no entheseal abnormalities were detected in group I while they were present in 23.3% of group II with statistically significant difference between them (P < 0.001). Ultrasonographic entheseal abnormalities were detected in 33.3% of group I and in 46.7% of group II with no significant difference between them (P > 0.05). Serum COMP were significantly elevated in group I and II with no statistically significant difference between them (mean ± SD 5.9 ± 3 and 6.8 ± 12 respectively, P > 0.05). Entheseal ultrasound was more specific (67%) while serum COMP was more sensitive (87%) in the preclinical diagnosis of psoriatic arthritis. Serum COMP levels were significantly correlated with CRP in both groups and with DAS28 and Steinbrockers scores in group II (P < 0.01). Conclusion: Entheseal ultrasonography and serum COMP levels may be used complementary to each other for preclinical diagnosis of psoriatic arthritis. Serum COMP seems to be promising prognostic marker for psoriatic arthritis patients.
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Cibere J, Zhang H, Garnero P, Poole AR, Lobanok T, Saxne T, Kraus VB, Way A, Thorne A, Wong H, Singer J, Kopec J, Guermazi A, Peterfy C, Nicolaou S, Munk PL, Esdaile JM. Association of biomarkers with pre-radiographically defined and radiographically defined knee osteoarthritis in a population-based study. ACTA ACUST UNITED AC 2009; 60:1372-80. [PMID: 19404937 DOI: 10.1002/art.24473] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To evaluate 10 biomarkers in magnetic resonance imaging (MRI)-determined, pre-radiographically defined osteoarthritis (pre-ROA) and radiographically defined OA (ROA) in a population-based cohort of subjects with symptomatic knee pain. METHODS Two hundred one white subjects with knee pain, ages 40-79 years, were classified into OA subgroups according to MRI-based cartilage (MRC) scores (range 0-4) and Kellgren/Lawrence (K/L) grades of radiographic severity (range 0-4): no OA (MRC score 0, K/L grade<2), pre-ROA (MRC score>or=1, K/L grade<2), or ROA (MRC score>or=1, K/L grade>or=2). Urine and serum samples were assessed for levels of the following biomarkers: urinary biomarkers C-telopeptide of type II collagen (uCTX-II), type II and types I and II collagen cleavage neoepitopes (uC2C and uC1,2C, respectively), and N-telopeptide of type I collagen, and serum biomarkers sC1,2C, sC2C, C-propeptide of type II procollagen (sCPII), chondroitin sulfate 846 epitope, cartilage oligomeric matrix protein, and hyaluronic acid. Multicategory logistic regression was performed to evaluate the association of OA subgroup with individual biomarker levels and biomarker ratios, adjusted for age, sex, and body mass index. RESULTS The risk of ROA versus no OA increased with increasing levels of uCTX-II (odds ratio [OR] 3.12, 95% confidence interval [95% CI] 1.35-7.21), uC2C (OR 2.13, 95% CI 1.04-4.37), and uC1,2C (OR 2.07, 95% CI 1.06-4.04), and was reduced in association with high levels of sCPII (OR 0.53, 95% CI 0.30-0.94). The risk of pre-ROA versus no OA increased with increasing levels of uC2C (OR 2.06, 95% CI 1.05-4.01) and uC1,2C (OR 2.06, 95% CI 1.12-3.77). The ratios of type II collagen degradation markers to collagen synthesis markers were better than individual biomarkers at differentiating the OA subgroups, e.g., the ratio of [uCTX-II][uC1,2C] to sCPII was associated with a risk of ROA versus no OA of 3.47 (95% CI 1.34-9.03) and a risk of pre-ROA versus no OA of 2.56 (95% CI 1.03-6.40). CONCLUSION Different cartilage degradation markers are associated with pre-ROA than are associated with ROA, indicating that their use as diagnostic markers depends on the stage of OA. Biomarker ratios contrasting cartilage degradation with cartilage synthesis are better able to differentiate OA stages compared with levels of the individual markers.
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Affiliation(s)
- Jolanda Cibere
- University of British Columbia, and Arthritis Research Centre of Canada, Vancouver General Hospital, Vancouver, British Columbia, Canada.
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Tseng S, Reddi AH, Di Cesare PE. Cartilage Oligomeric Matrix Protein (COMP): A Biomarker of Arthritis. Biomark Insights 2009; 4:33-44. [PMID: 19652761 PMCID: PMC2716683 DOI: 10.4137/bmi.s645] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Arthritis is a chronic disease with a significant impact on the population. It damages the cartilage, synovium, and bone of the joints causing pain, impairment, and disability in patients. Current methods for diagnosis of and monitoring the disease are only able to detect clinical manifestations of arthritis late in the process. However, with the recent onset of successful treatments for rheumatoid arthritis and osteoarthritis, it becomes important to identify prognostic factors that can predict the evolution of arthritis. This is especially critical in the early phases of disease so that these treatments can be started as soon as possible to slow down progression of the disease. A valuable approach to monitor arthritis would be by measuring biological markers of cartilage degradation and repair to reflect variations in joint remodeling. One such potential biological marker of arthritis is cartilage oligomeric matrix protein (COMP). In various studies, COMP has shown promise as a diagnostic and prognostic indicator and as a marker of the disease severity and the effect of treatment. This review highlights the progress in the utilization of COMP as a biomarker of arthritis.
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Affiliation(s)
- Susan Tseng
- Department of Orthopaedic Surgery, UC Davis Medical Center, Sacramento, California, 95817, U.S.A
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Ling SM, Patel DD, Garnero P, Zhan M, Vaduganathan M, Muller D, Taub D, Bathon JM, Hochberg M, Abernethy DR, Metter EJ, Ferrucci L. Serum protein signatures detect early radiographic osteoarthritis. Osteoarthritis Cartilage 2009; 17:43-8. [PMID: 18571442 PMCID: PMC2667202 DOI: 10.1016/j.joca.2008.05.004] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Accepted: 05/04/2008] [Indexed: 02/06/2023]
Abstract
OBJECTIVE To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident. METHODS Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques. RESULTS Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA. CONCLUSIONS Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.
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Affiliation(s)
- S M Ling
- National Institute on Aging Intramural Research Program, National Institutes of Health (NIH), Baltimore, MD 21225, United States.
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Nakajima S, Naruto T, Miyamae T, Imagawa T, Mori M, Nishimaki S, Yokota S. Improvement of reduced serum cartilage oligomeric matrix protein levels in systemic juvenile idiopathic arthritis patients treated with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol 2008; 19:42-6. [PMID: 18726067 DOI: 10.1007/s10165-008-0115-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Accepted: 07/17/2008] [Indexed: 10/21/2022]
Abstract
In this study, we determined serum cartilage oligomeric matrix protein (COMP) levels in systemic juvenile idiopathic arthritis (sJIA) patients during both the active and the remission phases to investigate how the growth cartilage turnover changed under tocilizumab treatment. Specimens were collected from 201 healthy children under 16 years of age with no growth impairment, and paired sera were collected from 11 sJIA patients treated with tocilizumab. Disease activity was assessed from white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and ferritin, and the COMP concentration was determined by sandwich enzyme-linked immunosorbent assay. Serum COMP concentrations were found independent of age, and the mean value in healthy children was 17.74+/-5.6 U/L. The mean serum COMP in sJIA patients during the active phase was 10.75+/-3.9 U/L, lower than that of healthy children. The mean serum COMP in the remission phase (14.89+/-3.9 U/L) was significantly higher than that in the active period (P<0.05). These results suggested that in sJIA patients, a reduced serum COMP concentration is a useful marker of active disease and growth impairment, and that the growth cartilage turnover suppressed during the active phase is improved in the remission phase under tocilizumab treatment.
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Affiliation(s)
- Shoko Nakajima
- Department of Pediatrics, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan
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Abstract
Treatment strategies for osteoarthritis most commonly involve the removal or replacement of damaged joint tissue. Relatively few treatments attempt to arrest, slow down or reverse the disease process. Such options include peri-articular osteotomy around the hip or knee, and treatment of femoro-acetabular impingement, where early intervention may potentially alter the natural history of the disease. A relatively small proportion of patients with osteoarthritis have a clear predisposing factor that is both suitable for modification and who present early enough for intervention to be deemed worthwhile. This paper reviews recent advances in our understanding of the pathology, imaging and progression of early osteoarthritis.
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Affiliation(s)
- T. C. B. Pollard
- Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, UK
| | - S. E. Gwilym
- Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, UK
| | - A. J. Carr
- Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, UK
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Fernandes FA, Pucinelli MLC, da Silva NP, Feldman D. Serum cartilage oligomeric matrix protein (COMP) levels in knee osteoarthritis in a Brazilian population: clinical and radiological correlation. Scand J Rheumatol 2007; 36:211-5. [PMID: 17657676 DOI: 10.1080/03009740601154186] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES In this study we present data on serum cartilage oligomeric matrix protein (COMP) levels in a Brazilian population with isolated knee osteoarthritis (OA) compared to healthy controls. Clinical and radiological correlations with COMP levels were also evaluated. METHODS Two hundred and seventy-two patients seen at the Rheumatology Division of the Federal University of São Paulo (UNIFESP) with a symptom of 'pain in the knees' for at least 3 months were invited to participate in this study. History and clinical examination were performed in all patients. Eighty-six patients with clinical isolated knee OA according to the American College of Rheumatology (ACR) criteria and without other causes of pain in the knee were included. Fifty-eight healthy individuals were selected, matched for age and sex, and used as controls. OA evaluation included Lequesne and Western Ontario and MacMaster Universities osteoarthritis index (WOMAC) questionnaires, visual analogue scale (VAS) for pain and standard knee X-rays. Blood samples were taken from all participants and serum COMP levels were measured by enzyme-linked immunosorbent assay (ELISA). OA radiological analysis was performed using the Kellgren and Lawrence (K/L) grading scale. RESULTS Patients with symptomatic knee OA presented significantly higher serum COMP levels compared to healthy controls and to those with non-symptomatic narrowing of the articular space (p<0.001). Patients with clinical evidence of knee OA and without radiological abnormalities (K/L grade 0 or 1) had intermediate serum COMP levels, significantly higher than those observed in healthy controls (p<0.03). CONCLUSIONS We observed increased serum COMP levels in patients with symptomatic radiological knee OA. High serum COMP levels may also indicate cartilage damage in selected symptomatic patients without significant radiological abnormalities.
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Affiliation(s)
- F A Fernandes
- Rheumatology Division, Federal University of São Paulo, School of Medicine (UNIFESP-EPM), São Paulo, Brazil.
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Rousseau JC, Delmas PD. Biological markers in osteoarthritis. ACTA ACUST UNITED AC 2007; 3:346-56. [PMID: 17538566 DOI: 10.1038/ncprheum0508] [Citation(s) in RCA: 161] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2006] [Accepted: 03/20/2007] [Indexed: 12/23/2022]
Abstract
Osteoarthritis (OA) is a progressive disorder characterized by destruction of articular cartilage and subchondral bone, and by synovial changes. The diagnosis of OA is generally based on clinical and radiographic changes, which occur fairly late during disease progression and have poor sensitivity for monitoring disease progression. Progression of joint damage is likely to result primarily from an imbalance between cartilage degradation and repair, so measuring markers of these processes would seem a promising approach to improve the prediction of disease progression at the individual level. Moreover, genetic markers might be useful predictors of prognosis. The lack of fully effective, chondroprotective medications has limited the use of such potential markers to monitor the effect of treatment for OA. Nevertheless, owing to their dynamic changes in response to treatment, biological markers might provide relevant information more rapidly than imaging techniques (such as radiography and MRI) can, and should contribute to our understanding of mechanisms that underlie the clinical efficacy of OA treatments. Most of the identified genes involved in OA encode signal-transduction proteins, which provide the potential for novel therapeutic approaches. In this Review, we will use the recently proposed BIPED (i.e. burden of disease, investigative, prognostic, efficacy of intervention and diagnostic) classification of OA markers to describe the potential usage of a given marker.
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Girling SL, Bell SC, Whitelock RG, Rayward RM, Thomson DG, Carter SC, Vaughan-Thomas A, Innes JF. Use of biochemical markers of osteoarthritis to investigate the potential disease-modifying effect of tibial plateau levelling osteotomy. J Small Anim Pract 2007; 47:708-14. [PMID: 17201821 DOI: 10.1111/j.1748-5827.2006.00150.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To evaluate the hypothesis that the concentration of the 1/20/5D4 epitope of keratan sulphate, cartilage oligomeric matrix protein and total sulphated glycosaminoglycans in synovial fluids from dogs with cranial cruciate ligament disease would be affected by tibial plateau levelling osteotomy. In addition, to evaluate the hypothesis that medial meniscal release or meniscal injury would alter the expression of these candidate biomarkers. METHODS Forty-one dogs with naturally occurring cranial cruciate ligament disease were recruited prospectively. Synovial fluids were collected from the index joint before surgery and six weeks and six months postsurgery. Following tibial plateau levelling osteotomy, synovial fluids were assayed for 1/20/5D4 epitope of keratan sulphate and cartilage oligomeric matrix protein concentration using an inhibition ELISA and for sulphated glycosaminoglycans using a direct dye-binding assay. RESULTS The sulphated glycosaminoglycans ratio did not change significantly during the study. Medial meniscal injury at entry was associated with lower concentrations of synovial fluid cartilage oligomeric matrix protein (P<0.05, unpaired t test). There was no association between medial meniscal release and the changes in marker concentrations, either from 0 to six weeks or 0 to six months. CLINICAL SIGNIFICANCE Tibial plateau levelling osteotomy did not significantly alter the expression of the named candidate biomarkers. These findings reflect the limited nature of the arthrotomy or indicate that tibial plateau levelling osteotomy does not influence the progression of osteoarthritis (OA). From these studies, there is no evidence that tibial plateau levelling osteotomy affects cartilage metabolism.
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Affiliation(s)
- S L Girling
- Small Animal Division, Faculty of Veterinary Science, University of Liverpool, Liverpool L69 0BX, UK
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Qi C, Changlin H. Effects of Moving Training on Histology and Biomarkers Levels of Articular Cartilage. J Surg Res 2006; 135:352-63. [PMID: 16904690 DOI: 10.1016/j.jss.2006.03.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2006] [Revised: 02/22/2006] [Accepted: 03/08/2006] [Indexed: 10/24/2022]
Abstract
OBJECTIVE To study the adaptation process and extent of articular cartilage in the canine knee joint to different modes of movements and to investigate if levels of cartilage oligomeric matrix protein (COMP), matrix metalloproteinases-1 (MMP-1), matrix metalloproteinases-3 (MMP-3), and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) in serum and synovial fluid can be used to predict effectively early sports injury and remolding degree of articular cartilage in the canine knee. MATERIALS AND METHODS Twenty adult dogs divided randomly into three groups (eight in the common training group, Training Group; eight in the intensified training group, Intensified Group; and four in the Control Group) were trained daily at different intensities. Magnetic resonance imaging (MRI) examinations were performed regularly (0, 2, 4, 6, 8, 10 weeks) to investigate changes of articular cartilage in the canine knee, while concentrations of COMP, MMP-1, MMP-3, and TIMP-1 in serum and synovial fluid were measured by ELISA assays. All of the dogs were euthanized after training for 10 weeks, and all of the knee joints were taken out to be examined histologically. RESULTS We could find imaging changes of early sport injury of articular cartilage in the Training Group and Intensified Group by MRI examination after 2 weeks of training; the damage images were most severe in 4-6 weeks, and then lightened gradually. We could not find the difference of cartilage injury and repair degree in MRI images between these two groups at different time points. Elevations of levels of COMP, MMP-1, MMP-3, TIMP-1, and MMP-3/TIMP-1 in serum and synovial fluid were seen during the training period, and their levels changed remarkably at different times. Levels of MMP-1, MMP-3, and MMP-3/TIMP-1 in the Intensified Group were lower than that in the Training Group in general, and levels of COMP were higher, which hinted that the injury trend of articular cartilage in the Intensified Group was lower than that in the Training group, and the repair trend was higher. Furthermore, there were statistically significant associations between biomarker levels in serum and in synovial fluid. Histological examinations in 10 weeks demonstrated that the signs of cartilage damage and repair in canine knee joint in the Training Group and the Intensified Group were obvious, and the Intensified Group could do better than the Training Group in promoting remodeling reconstruction of articular cartilage. CONCLUSIONS High-intensity and repetitive movement may easily induce sports injury, and it is followed with a repair process; intensified training can do better than common training in promoting remodeling reconstruction of articular cartilage. The sensitivity of these biomarkers reflecting articular cartilage pathological changes is better than MRI, and the associated application of several biomarkers to predict the extent of damage and repair, as well as changes of metabolism in articular cartilage, and to monitor change of disease course has very good value for clinical application.
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Affiliation(s)
- Chang Qi
- Orthopedics Institute, Xijing Hospital of PLA, Fourth Military Medical University, Xi'an, Shaanxi Province, China
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Punzi L, Oliviero F, Plebani M. New biochemical insights into the pathogenesis of osteoarthritis and the role of laboratory investigations in clinical assessment. Crit Rev Clin Lab Sci 2005; 42:279-309. [PMID: 16281737 DOI: 10.1080/10408360591001886] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Osteoarthritis (OA) is among the most frequent diseases in the population and a common cause of pain and disability in adults. The principal disease hallmarks for assessment of OA are still clinical observation and radiographic aspects. However, the efficacy of therapeutic interventions is complicated by the time required to observe radiographic signs, useful for both diagnosis and assessment. Thus, laboratory markers have received growing attention in recent years, in an attempt to improve diagnosis, assessment of disease activity and severity, and evaluation of therapeutic effects. Many biomarkers have been proposed, in particular those reflecting cartilage and bone turnover and synovitis. Among these, COMP, antigenic keratan sulphate, hyaluronan, YKL-40, type III collagen N-propeptide, and urinary glucosyl-galactosyl pyridinoline appear to be the most promising. However, serum or urinary determinations of these molecules are difficult to interpret adequately due to their complex metabolism. New ultrasensitive methods for C-reactive protein have improved the usefulness of this marker, especially in the assessment of disease activity. Routine examination of synovial fluid is still essential for diagnosis and includes leukocyte count and crystal detection; specialized testing includes the evaluation of the levels of markers of local inflammation such as metalloproteinases and cytokines, which appear to be crucial to the pathogenesis of OA.
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Kelman A, Lui L, Yao W, Krumme A, Nevitt M, Lane NE. Association of higher levels of serum cartilage oligomeric matrix protein and N-telopeptide crosslinks with the development of radiographic hip osteoarthritis in elderly women. ACTA ACUST UNITED AC 2005; 54:236-43. [PMID: 16385523 DOI: 10.1002/art.21527] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
OBJECTIVE To examine the association of baseline concentrations of serum cartilage oligomeric matrix protein (COMP) and serum N-telopeptide crosslinks (NTX) with the development and progression of radiographic hip osteoarthritis (RHOA) in elderly women. METHODS Pelvic radiographs were obtained a mean of 8.3 years apart from white women > or =65 years of age enrolled in the Study of Osteoporotic Fractures. Random sampling from a cohort of 5,928 subjects was performed, with subjects ( approximately 200 per group) assigned to nested case-control studies, one focusing on RHOA incidence and the other on RHOA progression. Baseline serum levels of COMP and NTX were measured by enzyme-linked immunosorbent assay in duplicate. Odds ratios (ORs) and 95% confidence intervals (95% CIs), indicating the likelihood of baseline serum COMP and NTX levels to be predictive of the development or progression of RHOA, were calculated using logistic regression analysis, with adjustment for potential covariates. RESULTS At baseline, incident cases of RHOA were associated with higher serum levels of COMP and NTX (P < 0.05 for each) compared with the no RHOA control group. Higher baseline serum COMP and NTX levels were associated with an increased risk of incident RHOA compared with the no RHOA group, with an adjusted OR of 1.31 per SD increase in COMP (95% CI 1.02-1.68) and adjusted OR of 1.38 per SD increase in NTX (95% CI 1.07-1.79). In this community-based cohort, progression of RHOA was modest. However, there was a trend toward increased risk of RHOA progression with higher baseline COMP and NTX levels. CONCLUSION These data suggest that serum levels of COMP and NTX are modest risk markers for the development of RHOA in a community-based cohort of elderly white women.
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Affiliation(s)
- A Kelman
- Stanford University Medical Center, Stanford, California, USA
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Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, Rodan GA, Duong LT. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. ACTA ACUST UNITED AC 2004; 50:1193-206. [PMID: 15077302 DOI: 10.1002/art.20124] [Citation(s) in RCA: 435] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE It has been suggested that subchondral bone remodeling plays a role in the progression of osteoarthritis (OA). To test this hypothesis, we characterized the changes in the rat anterior cruciate ligament transection (ACLT) model of OA and evaluated the effects of alendronate (ALN), a potent inhibitor of bone resorption, on cartilage degradation and on osteophyte formation. METHODS Male Sprague-Dawley rats underwent ACLT or sham operation of the right knee. Animals were then treated with ALN (0.03 and 0.24 microg/kg/week subcutaneously) and necropsied at 2 or 10 weeks postsurgery. OA changes were evaluated. Subchondral bone volume and osteophyte area were measured by histomorphometric analysis. Coimmunostaining for transforming growth factor beta (TGF beta), matrix metalloproteinase 9 (MMP-9), and MMP-13 was performed to investigate the effect of ALN on local activation of TGF beta. RESULTS ALN was chondroprotective at both dosages, as determined by histologic criteria and collagen degradation markers. ALN suppressed subchondral bone resorption, which was markedly increased 2 weeks postsurgery, and prevented the subsequent increase in bone formation 10 weeks postsurgery, in the untreated tibial plateau of ACLT joints. Furthermore, ALN reduced the incidence and area of osteophytes in a dose-dependent manner. ALN also inhibited vascular invasion into the calcified cartilage in rats with OA and blocked osteoclast recruitment to subchondral bone and osteophytes. ALN treatment reduced the local release of active TGF beta, possibly via inhibition of MMP-13 expression in articular cartilage and MMP-9 expression in subchondral bone. CONCLUSION Subchondral bone remodeling plays an important role in the pathogenesis of OA. ALN or other inhibitors of bone resorption could potentially be used as disease-modifying agents in the treatment of OA.
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Affiliation(s)
- Tadashi Hayami
- Merck Research Laboratories, West Point, Pennsylvania 19486, USA
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Christgau S, Cloos PA. Cartilage degradation products as markers for evaluation of patients with rheumatic disease. ACTA ACUST UNITED AC 2004. [DOI: 10.1016/j.cair.2004.01.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Lohmander LS, Atley LM, Pietka TA, Eyre DR. The release of crosslinked peptides from type II collagen into human synovial fluid is increased soon after joint injury and in osteoarthritis. ACTA ACUST UNITED AC 2003; 48:3130-9. [PMID: 14613275 DOI: 10.1002/art.11326] [Citation(s) in RCA: 182] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
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.
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Poole AR. Biochemical/immunochemical biomarkers of osteoarthritis: utility for prediction of incident or progressive osteoarthritis. Rheum Dis Clin North Am 2003; 29:803-18. [PMID: 14603584 DOI: 10.1016/s0889-857x(03)00056-5] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In this brief review the authors endeavored to show how methods developed for molecular studies of the development, onset, and progression of OA have been used to develop biomarker assays that might be of use in the detection of incident OA and in progression of established OA (Fig. 2). These assays involve analyses of specific molecular products in body fluids that result from the cleavage and synthesis of molecules in specific skeletal tissues and from inflammatory processes associated with OA joint disease. These assays are proving to be of value in the detection, study, and treatment of OA, especially with respect to improving understanding of the pathology of the disease and how it can best be detected and managed. Such assays also offer the potential to develop much shorter, more efficient, and cost effective clinical trials for the evaluation of potential disease-modifying therapies for OA.
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Affiliation(s)
- A Robin Poole
- Joint Diseases Laboratory, Shriners Hospitals for Children, Department of Surgery, Department of Medicine, McGill University, Montreal, Quebec, Canada.
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Affiliation(s)
- F A Wollheim
- Department of Rheumatology, University of Lund Hospital, Sweden.
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48
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Abstract
PURPOSE OF REVIEW Osteoarthritis is a chronic disease characterized by progressive destruction of articular cartilage and subchondral bone, and synovial reaction. Clinical and radiologic findings that form the basis of the diagnosis of osteoarthritis are poorly sensitive for monitoring the progression of the disease. Biologic markers reflecting quantitative and dynamic changes of joint tissue turnover represent promising adjunct tools. RECENT FINDINGS New tissue-specific markers have been developed and include assays for type II collagen synthesis and degradation and synovitis. Prospective studies indicate that increased or decreased levels of some of these markers are associated with rapid progression of joint destruction in patients with knee osteoarthritis. Because progression of joint damage is likely to result primarily from an imbalance between degradation and reparative processes, a combination of markers reflecting these two components appears promising. For example, combining two new markers for type II collagen synthesis and degradation in an uncoupling index of cartilage turnover was more effective in predicting 1-year radiologic progression in knee osteoarthritis than the measurement of a single marker. Preliminary data in rheumatoid arthritis show a rapid response of a marker of type II collagen degradation under disease-modifying antirheumatic drugs, with early changes of this marker being predictive of long-term radiologic progression. SUMMARY Recent evidence suggests that the combination of some biologic markers will be useful for identifying patients at risk for rapid joint destruction in osteoarthritis. Because of their rapid changes under treatment, biologic markers will play an important role in the development and monitoring of new structure-modifying therapies for osteoarthritis.
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Bobacz K, Maier R, Fialka C, Ekhart H, Woloszczuk W, Geyer G, Erlacher L, Smolen J, Graninger WB. Is pro-matrix metalloproteinase-3 a marker for posttraumatic cartilage degradation? Osteoarthritis Cartilage 2003; 11:665-72. [PMID: 12954237 DOI: 10.1016/s1063-4584(03)00159-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Since the development of posttraumatic osteoarthritis (OA) is a relatively slow process, estimation of OA risk would be of value with regard to chondroprotective measures and medication. In this study we investigated the significance of pro-matrixmetalloproteinase-3 (proMMP-3) for this purpose. DESIGN Synovial fluid (SF) and serum samples were collected from 259 patients of our trauma clinic at the time of arthroscopy. The extent of cartilage damage was assessed according to the Outerbridge-score. ProMMP-3 levels in SF and serum were determined by enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody. Additionally we determined SF and serum levels of total MMP-3 and COMP levels as well as TIMP-1 and -2 concentrations in 40 randomly selected patients by ELISA. RESULTS Serum proMMP-3 levels of the total cohort were markedly increased compared to healthy controls (P<0.007). The comparison of serum and SF lavage proMMP-3 concentrations showed a significant correlation (r(s)=0.41, P<0.0001), however, only 26% of the investigated samples were increased above normal ranges. The grade of cartilage damage did not correlate with enzyme concentration neither in patients' serum nor in SF samples. ProMMP-3 SF concentration was increased early after trauma. Furthermore, proMMP-3 correlated significantly with total MMP-3 serum and SF levels as well as COMP SF levels. CONCLUSIONS The measurement of proMMP-3 in serum or SF did not reflect the present cartilage damage and thus appears to have only minor potential for clinical use, but it should be considered for longitudinal studies, since it may reflect a risk for cartilage degradation in a subset of patients.
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Affiliation(s)
- K Bobacz
- Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Vienna, Austria
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