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Neto M, Mendes B, Albuquerque F, da Silva JAP. Novel biomarkers in RA: Implication for diagnosis, prognosis, and personalised treatment. Best Pract Res Clin Rheumatol 2024:102021. [PMID: 39550250 DOI: 10.1016/j.berh.2024.102021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 11/18/2024]
Abstract
Over the past decades our understanding of rheumatoid arthritis (RA) pathogenesis has improved remarkably and major breakthroughs in the treatment of RA were made with the advent of numerous targeted therapies and new treatment strategies. Despite these advances, several unmet needs remain, namely in achieving earlier and more accurate diagnosis, monitoring disease activity, predicting disease prognosis and optimizing treatment. To address these gaps, recent research has focused on identifying biomarkers that may enhance diagnostic precision, predict disease prognosis, and optimize treatment strategies. In this narrative review we will describe recent developments in RA biomarkers with demonstrated or promising clinical relevance.
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Affiliation(s)
- Marcelo Neto
- Rheumatology Department, Unidade Local de Saúde de Coimbra, Portugal.
| | - Beatriz Mendes
- Rheumatology Department, Unidade Local de Saúde de Coimbra, Portugal.
| | | | - José António P da Silva
- Rheumatology Department, Unidade Local de Saúde de Coimbra, Portugal; Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Portugal.
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Szeremeta A, Jura-Półtorak A, Zoń-Giebel A, Olczyk K, Komosińska-Vassev K. Effects of Etanercept and Adalimumab on Serum Levels of Cartilage Remodeling Markers in Women with Rheumatoid Arthritis. J Clin Med 2023; 12:5185. [PMID: 37629227 PMCID: PMC10455345 DOI: 10.3390/jcm12165185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/31/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
Tumor necrosis factor α inhibitor (TNFαI) therapy is associated with a significant inhibition of radiographic progression, resulting in improved physical function and quality of life among patients with rheumatoid arthritis (RA). The mechanism by which TNFαI prevent joint destruction is still unknown. In this study, the effect of 15-month anti-TNF-α therapy in combination with methotrexate on circulating levels of biochemical markers of cartilage turnover in female RA patients was assessed. Serum levels of collagen type II C-terminal cleavage neoepitope (C2C), C-terminal propeptide of type II collagen (PIICP), cartilage oligomeric matrix protein (COMP), and matrix metalloproteinase-3 (MMP-3) were evaluated using immunoassays at baseline and 15 months after the start of TNFαI treatment. Baseline COMP, C2C, and MMP-3 levels and C2C/PIICP ratios were significantly higher in women with RA compared with those observed in the healthy subjects. No differences in PIICP levels between the controls and the women with RA were observed. After 15 months of TNFαI treatment, serum levels of C2C, COMP, and MMP-3 decreased, whereas the levels of PIICP increased but were still not different from those of the controls. These changes were accompanied by significantly reduced C2C/PIICP ratios. Before the start of TNFαI therapy, serum levels of COMP significantly correlated with the patients' ages (p < 0.05) and their 28-joint disease activity score values based on their erythrocyte sedimentation rates (DAS28-ESR; p < 0.05). Moreover, multiple linear regression analysis showed that baseline COMP levels retained a significant association with DAS28-ESR value (β = 287.74, p = 0.022, R2 model = 0.25) after model adjustments. The largest area under the ROC curve was obtained for C2C/PIICP ratios (AUC: 0.830, 95% CI: 0.727-0.932, p < 0.001). Our results suggest that long-term anti-TNF-α therapy combined with MTX has a beneficial effect on cartilage remodeling that is associated with clinical improvement among RA patients. Serum C2C/PIICP ratios may help to monitor the effectiveness of anti-TNF-α treatment among RA patients.
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Affiliation(s)
- Anna Szeremeta
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| | - Agnieszka Jura-Półtorak
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| | - Aleksandra Zoń-Giebel
- Department of Rheumatology and Rehabilitation, Specialty Hospital No. 1, Żeromskiego 7, 41-902 Bytom, Poland;
| | - Krystyna Olczyk
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
| | - Katarzyna Komosińska-Vassev
- Department of Clinical Chemistry and Laboratory Diagnostics, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland; (A.J.-P.); (K.O.); (K.K.-V.)
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Alape D, Singh R, Folch E, Fernandez Bussy S, Agnew A, Majid A. Life-Threatening Multilevel Airway Stenosis Due to Myhre Syndrome. Am J Respir Crit Care Med 2020; 201:731-732. [PMID: 31539271 DOI: 10.1164/rccm.201905-0922im] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Daniel Alape
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center and.,Department of Internal Medicine, UMass Memorial Medical Center, University of Massachusetts Medical School, Worcester, Massachusetts; and
| | - Rani Singh
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center and
| | - Erik Folch
- Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Alexis Agnew
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center and
| | - Adnan Majid
- Division of Thoracic Surgery and Interventional Pulmonology, Beth Israel Deaconess Medical Center and
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Caliskan T, Sirin DY, Karaarslan N, Yilmaz I, Ozbek H, Akyuva Y, Kaplan N, Kaya YE, Simsek AT, Guzelant AY, Ates O. Effects of etanercept, a tumor necrosis factor receptor fusion protein, on primary cell cultures prepared from intact human intervertebral disc tissue. Exp Ther Med 2019; 18:69-76. [PMID: 31258639 PMCID: PMC6566078 DOI: 10.3892/etm.2019.7559] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 02/06/2019] [Indexed: 02/06/2023] Open
Abstract
The aim of the present study was to investigate the effects of etanercept (ETA), a tumor necrosis factor (TNF) inhibitor, on human cell cultures prepared from intact intervertebral disc tissue. ETA is used as a treatment for cases of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis accompanied by moderate or severe joint pain. ETA was applied to primary cell cultures [annulus fibrosus and nucleus pulposus (NP) from intact intervertebral disc tissue]. Cell cultures without ETA treatment served as the control group. Morphological and quantitative molecular analyses of the two groups were performed. The number of viable cells and cell proliferation decreased in the ETA-treated cultures as compared with those in the control group. Furthermore, in the treatment group, the chondroadherin gene, an NP-specific marker, was not expressed after 24 h. By contrast, the cartilage oligo matrix protein was expressed 24, 48 and 72 h post-ETA treatment, while its expression was significantly lower than that in the control group. In addition, the expression of interleukin-1β, as well as matrix metallopeptidase-7 and -19, was markedly decreased. Overall, the cell proliferation and gene expression in the ETA-treated cells were significantly different from those in the control group (P<0.05). These results suggest that the treatment duration and dosage of TNF inhibitors, which are used to suppress active inflammation, should be considered in the clinical setting. These biological agents may delay the healing of intervertebral disc tissue damage by slowing cell proliferation and altering gene expression via anabolic and catabolic pathways.
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Affiliation(s)
- Tezcan Caliskan
- Department of Neurosurgery, Namik Kemal University School of Medicine, Tekirdag 59100, Turkey
| | - Duygu Yasar Sirin
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Namik Kemal University, Tekirdag 59100, Turkey
| | - Numan Karaarslan
- Department of Neurosurgery, Namik Kemal University School of Medicine, Tekirdag 59100, Turkey
| | - Ibrahim Yilmaz
- Department of Medical Pharmacology, Istanbul Medipol University School of Medicine, Istanbul 34810, Turkey
| | - Hanefi Ozbek
- Department of Medical Pharmacology, Istanbul Medipol University School of Medicine, Istanbul 34810, Turkey
| | - Yener Akyuva
- Department of Neurosurgery, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul 34433, Turkey
| | - Necati Kaplan
- Department of Neurosurgery, Corlu Reyap Hospital, Istanbul Rumeli University, Tekirdag 59680, Turkey
| | - Yasin Emre Kaya
- Department of Orthopedic and Traumatology, Abant Izzet Basal University School of Medicine, Bolu 14000, Turkey
| | - Abdullah Talha Simsek
- Department of Neurosurgery, Namik Kemal University School of Medicine, Tekirdag 59100, Turkey
| | - Aliye Yildirim Guzelant
- Department of Physical Medicine and Rehabilitation, Corlu Reyap Hospital, Istanbul Rumeli University, Tekirdag 59680, Turkey
| | - Ozkan Ates
- Department of Neurosurgery, Esencan Hospital, Istanbul Esenyurt University, Istanbul 34570, Turkey
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Chu P, Wang Q, Wang Z, Gao C. Long non-coding RNA highly up-regulated in liver cancer protects tumor necrosis factor-alpha-induced inflammatory injury by down-regulation of microRNA-101 in ATDC5 cells. Int Immunopharmacol 2019; 72:148-158. [PMID: 30981080 DOI: 10.1016/j.intimp.2019.04.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 01/09/2019] [Accepted: 04/02/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Osteoarthritis (OA) is a familiar joint degenerative disease. Long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of OA. Nevertheless, the regulatory impacts of lncRNA highly up-regulated in liver cancer (lncRNA-HULC) on OA remain dimness. The study tried to probe the protective effect of HULC on ATDC5 cells against tumor necrosis factor-alpha (TNF-α)-induced inflammatory injury. METHODS Relative expression levels of pro-inflammatory cytokines (IL-6, IL-8 and MCP-1) and HULC in OA cartilage tissues and normal cartilage tissues were determined by RT-qPCR. TNF-α induced inflammatory injury model in ATDC5 cells was constructed, and the biological functions of HULC overexpression or suppression in TNF-α-injured ATDC5 cells were assessed. The relevancy between miR-101 and HULC was investigated by utilizing bioinformatics prediction, luciferase reporter assay, RNA pull-down and immunoprecipitation. MiR-101 mimic and inhibitor were transfected into ATDC5 cells, and its regulatory effect on TNF-α-injured ATDC5 cells was examined. Further, NF-κB and MAPK signaling pathways were finally detected by western blot. RESULTS Enhancement of IL-6, IL-8 and MCP-1 were observated in OA cartilage tissues, but repression of HULC was discovered in OA cartilage tissues. HULC expression was decreased by TNF-α treatment, and overexpressed HULC significantly relieved TNF-α-induced ATDC5 cells injury. Additionally, miR-101 was mutual repressed with HULC, and overexpressed miR-101 reversed the protective effect of HULC in TNF-α-injured ATDC5 cells. Besides, HULC blocked NF-κB and MAPK pathways via repression of miR-101. CONCLUSIONS The discoveries testified that HULC protected ATDC5 cells against TNF-α-induced inflammatory injury by repression of miR-101.
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Affiliation(s)
- Peigang Chu
- The Second Hospital of Shandong University, Jinan 250000, China
| | - Qiang Wang
- Department of Joint Surgery, Taian City Central Hospital, Taian 271000, China
| | - Zongru Wang
- Second Department of Orthopedics, The First People's Hospital of Taian, Taian 271000, China
| | - Chunzheng Gao
- The Second Hospital of Shandong University, Jinan 250000, China.
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Andréasson K, Jönsson G, Hesselstrand R, Norrgren H. Persistent elevation of fibrosis biomarker cartilage oligomeric matrix protein following hepatitis C virus eradication. World J Hepatol 2019; 11:330-334. [PMID: 30967910 PMCID: PMC6447423 DOI: 10.4254/wjh.v11.i3.330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Revised: 02/27/2019] [Accepted: 03/16/2019] [Indexed: 02/06/2023] Open
Abstract
Serum levels of cartilage oligomeric matrix protein (COMP) has been presented as a biomarker of liver fibrosis in several cross-sectional studies. COMP is also an essential mediator in carcinoma development and has also been associated with hepatocellular carcinoma. We present a prospective analysis of this biomarker in 38 patients with chronic hepatitis C who were subject to eradication therapy with direct acting antivirals. We confirm previous studies associating COMP elevation with liver cirrhosis. We also show how viral levels are correlated with COMP at baseline. In our prospective analysis, we report that successful eradication of hepatitis C results in improvement in liver stiffness and laboratory liver function tests at 1 year follow-up. In contrast, median COMP-levels remain unchanged during the study period. We conclude that the biomarker potential of COMP in the prospective evaluation of liver diseases, remains to be elucidated.
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Affiliation(s)
- Kristofer Andréasson
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund S-221 85, Sweden
| | - Göran Jönsson
- Section of Infectious Diseases, Department of Clinical Sciences Lund, Lund University, Lund S-221 85, Sweden
| | - Roger Hesselstrand
- Section of Rheumatology, Department of Clinical Sciences Lund, Lund University, Lund S-221 85, Sweden
| | - Hans Norrgren
- Section of Infectious Diseases, Department of Clinical Sciences Lund, Lund University, Lund S-221 85, Sweden
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Role of cartilage oligomeric matrix protein (COMP) as a prognostic biomarker in follow-up of early rheumatoid arthritis patients: Correlation to musculoskeletal ultrasonographic findings. EGYPTIAN RHEUMATOLOGIST 2018. [DOI: 10.1016/j.ejr.2018.01.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Morita M, Yamada K, Date H, Hayakawa K, Sakurai H, Yamada H. Efficacy of Chondroitin Sulfate for Painful Knee Osteoarthritis: A One-Year, Randomized, Double-Blind, Multicenter Clinical Study in Japan. Biol Pharm Bull 2018; 41:163-171. [DOI: 10.1248/bpb.b17-00556] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Affiliation(s)
| | - Kotaro Yamada
- Consumer Healthcare Products Development, Zeria Pharmaceutical Co., Ltd
| | - Hideki Date
- Department of Orthopaedic Surgery, Fujita Health University
| | - Kazue Hayakawa
- Department of Orthopaedic Surgery, Fujita Health University
| | - Hidetomo Sakurai
- Consumer Healthcare Products Development, Zeria Pharmaceutical Co., Ltd
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Lipina M, Makarov M, Makarov S, Novikov A. The degree of cartilage degradation assessed by serum biomarker levels changes after arthroscopic knee synovectomy in rheumatoid arthritis patients. INTERNATIONAL ORTHOPAEDICS 2017; 41:2259-2264. [PMID: 28889180 DOI: 10.1007/s00264-017-3634-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 08/28/2017] [Indexed: 10/18/2022]
Abstract
PURPOSE In order to test the validity of the selected surgical technique as a way to manage persistent synovitis of the knee joint, as well as to slow down the cartilage and bone destruction, we studied the dynamics of biomarkers of inflammatory conditions, and bone and cartilage destruction after total arthroscopic synovectomy (TAS) of the knee joint. METHODS The sampling comprised 124 RA patients (158 knees) who had undergone the TAS procedure between 2003 and 2015. Before surgery the rheumatoid factor (IgM), C-reactive protein (CRP), erythrocyte sedimentation rate test was completed for all patients. Blood serum samples were collected (prior to surgery, and three, six and 12 months after surgery) and frozen at -70°С. The content of CRP, Matrix metalloproteinase-3 (MMP-3), Cartilage Oligomeric Matrix Protein, as well as cross-linked Ctelopeptides of types I and II were measured in blood serum by means of polarization fluoroimmunoassay with the use of a standard set of reagents. RESULTS The average duration of the disease in the studied group was 8.7 ± 6.6 years. Concentration of the inflammation markers showed that only MMP-3 displayed statistical significance. CONCLUSIONS The obtained results can be used as basis in assessing the efficiency and effectiveness of this method of treatment of persistent knee joint synovitis associated with the RA.
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Affiliation(s)
- Marina Lipina
- V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation.
| | - Maxim Makarov
- V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation
| | - Sergey Makarov
- V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation
| | - Alexander Novikov
- V.A. Nasonova Research Institute of Rheumatology, Moscow, Russian Federation
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Sakthiswary R, Rajalingam S, Hussein H, Sridharan R, Asrul AW. Cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis and its correlation with sonographic knee cartilage thickness and disease activity. Clin Rheumatol 2017; 36:2683-2688. [DOI: 10.1007/s10067-017-3817-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2016] [Revised: 08/09/2017] [Accepted: 09/01/2017] [Indexed: 01/04/2023]
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Serum and synovial cartilage oligomeric matrix protein levels in early and established rheumatoid arthritis. Z Rheumatol 2017; 75:917-923. [PMID: 26683321 DOI: 10.1007/s00393-015-1647-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
OBJECTIVE To assess cartilage oligomeric matrix protein (COMP) levels in serum and synovial fluid in patients with early and established rheumatoid arthritis (RA), and to correlate the levels with clinical, laboratory and radiological characteristics. PATIENTS AND METHODS The study included 24 female RA patients. Full medical history was taken, thorough clinical examination and laboratory investigations performed, and body mass index (BMI) recorded. Radiological damage was assessed according to the modified Larsen score. Disease activity score 28 (DAS28) was calculated. The control group comprised 30 age- and gender-matched healthy subjects. Serum and synovial COMP levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS Mean patient age was 44.04 ± 10.5 years. Of the 24 patients, 12 had early RA and 12 had established disease with joint destruction; 5 of each group had knee effusion. Serum COMP was significantly higher in patients (19.54 ± 5.47 µg/ml) compared to controls (5.93 ± 1.95 µg/ml; p < 0.001) and was also significantly higher in patients with established disease (23.9 ± 3.1 µg/ml) compared to those in early stages (15.1 ± 3.2 µg/ml; p < 0.001). Synovial COMP was also significantly increased in established compared to early-stage RA (31.2 ± 9.8 µg/ml vs. 51.6 ± 10.4 µg/ml; p = 0.013). Serum and synovial COMP significantly correlated with age, disease duration, BMI, DAS28 and modified Larsen score. On performing regression analysis in RA patients, only BMI could predict the serum level of COMP (p = 0.02). CONCLUSION COMP is a promising biomarker for disease activity in RA, making it a potential therapeutic target. The obvious correlation with the BMI throws light on the importance of weight control not only in osteoarthritis (OA), but also in RA.
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Wedekind KJ, Ruff KJ, Atwell CA, Evans JL, Bendele AM. Beneficial effects of natural eggshell membrane (NEM) on multiple indices of arthritis in collagen-induced arthritic rats. Mod Rheumatol 2016; 27:838-848. [PMID: 27846748 DOI: 10.1080/14397595.2016.1259729] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
OBJECTIVES This study was performed to evaluate the potential efficacy of natural eggshell membrane (NEM) in collagen-induced arthritic rats, a well-established rodent model of inflammation and rheumatoid arthritis. METHODS Rats with developing type II collagen-induced arthritis (CIA) were treated once daily by oral gavage on study days -14 to 17 with vehicle or NEM (52 mg/kg body weight). Rats were euthanized on study day 17. Efficacy was assessed by daily ankle caliper measurements, ankle diameter expressed as area under the curve (AUCd0-17), and histopathologic evaluation of ankles and knees. Serum biomarkers of cartilage function and inflammation [collagen type II C-telopeptide (CTXII), cartilage oligomeric matrix protein (COMP), and alpha-2-macroglobulin (A2M)] were measured by ELISA. RESULTS Treatment with NEM resulted in significant beneficial effects on the daily ankle diameter measurements and ankle diameter AUC. Ankle and knee histopathology scores were significantly reduced (36% and 43% reduction of summed individual histopathology scores for ankle and knee, respectively; p < 0.05) toward normal for rats given NEM compared to vehicle controls. The percent reduction of serum CTXII, COMP, and A2M in NEM-treated rats ranged from 30% to 72% (p < 0.05). CONCLUSIONS NEM significantly improved multiple aspects of inflammatory arthritis including inflammation, pannus, cartilage damage, bone resorption, and periosteal bone formation. This study provides further support for the use of CTXII, COMP, and A2M as relevant biomarkers that were responsive to NEM.
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Affiliation(s)
- Karen J Wedekind
- a Research and Development Department , Novus International , St. Charles , MO , USA
| | | | - Cindy A Atwell
- a Research and Development Department , Novus International , St. Charles , MO , USA
| | - Joseph L Evans
- c P and N Development Ventures , St. Louis , MO , USA , and
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Magdaleno F, Arriazu E, Ruiz de Galarreta M, Chen Y, Ge X, Conde de la Rosa L, Nieto N. Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis. J Hepatol 2016; 65:963-971. [PMID: 27318326 PMCID: PMC5831373 DOI: 10.1016/j.jhep.2016.06.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 05/30/2016] [Accepted: 06/08/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Liver fibrosis is characterized by significant accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen-I, as a result of persistent liver injury. Cartilage oligomeric matrix protein (COMP) is largely found in the ECM of skeletal tissue. Increased COMP expression has been associated with fibrogenesis in systemic sclerosis, lung fibrosis, chronic pancreatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that COMP could induce fibrillar collagen-I deposition and participate in matrix remodeling thus contributing to the pathophysiology of liver fibrosis. METHODS Thioacetamide (TAA) and carbon tetrachloride (CCl4) were used to induce liver fibrosis in wild-type (WT) and Comp-/- mice. In vitro experiments were performed with primary hepatic stellate cells (HSCs). RESULTS COMP expression was detected in livers from control WT mice and was upregulated in response to either TAA or CCl4-induced liver fibrosis. TAA-treated or CCl4-injected Comp-/- mice showed less liver injury, inflammation and fibrosis compared to their corresponding control WT mice. Challenge of HSCs with recombinant COMP (rCOMP) induced intra- plus extracellular collagen-I deposition and increased matrix metalloproteinases (MMPs) 2, 9 and 13, albeit similar expression of transforming growth factor beta (TGFβ) protein, in addition to Tgfβ, tumour necrosis factor alpha (Tnfα) and tissue inhibitor of metalloproteinases-1 (Timp1) mRNAs. We demonstrated that COMP binds collagen-I; yet, it does not prevent collagen-I cleavage by MMP1. Last, rCOMP induced collagen-I expression in HSCs via CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway. CONCLUSION These results suggest that COMP contributes to liver fibrosis by regulating collagen-I deposition. LAY SUMMARY Cartilage oligomeric matrix protein (COMP) induces fibrillar collagen-I deposition via the CD36 receptor signaling and activation of the MEK1/2-pERK1/2 pathway, and participates in extracellular matrix remodeling contributing to the pathophysiology of liver fibrosis.
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Affiliation(s)
- Fernando Magdaleno
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10029, USA; Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Elena Arriazu
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10029, USA
| | - Marina Ruiz de Galarreta
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10029, USA
| | - Yu Chen
- Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Xiaodong Ge
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10029, USA; Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA
| | - Laura Conde de la Rosa
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10029, USA
| | - Natalia Nieto
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, Box 1123, 1425 Madison Avenue, Room 11-70, New York, NY 10029, USA; Department of Pathology, University of Illinois at Chicago, 840 S. Wood St., Suite 130 CSN, MC 847, Chicago, IL 60612, USA.
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Lewander P, Dahle C, Larsson B, Wetterö J, Skogh T. Circulating cartilage oligomeric matrix protein in juvenile idiopathic arthritis. Scand J Rheumatol 2016; 46:194-197. [PMID: 27385219 DOI: 10.1080/03009742.2016.1192681] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVES Raised serum cartilage oligomeric matrix protein (sCOMP) has been reported to predict erosive disease in early rheumatoid arthritis (RA). In juvenile idiopathic arthritis (JIA), subnormal sCOMP levels have been associated with ongoing inflammation and growth retardation. In this study we aimed to assess sCOMP, C-reactive protein (CRP), and insulin-like growth factor (IGF)-1 in children/adolescents with JIA and in referents. METHOD We enrolled 52 JIA patients at planned outpatient visits and 54 inpatients with ongoing infection ('infection referents'). A total of 120 referents testing negative for immunoglobulin (Ig)E-mediated allergy ('IgE referents') served as controls. All serum samples were analysed for COMP, IGF-1, and CRP. RESULTS The average sCOMP level was highest among the IgE referents and lowest among the infection referents. In the JIA patients, the level of sCOMP was not associated with the level of CRP or with clinical signs of disease activity. CONCLUSIONS The results of this study do not support routine clinical analysis of sCOMP levels in patients with JIA.
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Affiliation(s)
- P Lewander
- a Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine , Faculty of Medicine and Health Sciences, Linköping University , Linköping , Sweden.,b Department of Paediatrics , County Council of Östergötland , Sweden
| | - C Dahle
- a Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine , Faculty of Medicine and Health Sciences, Linköping University , Linköping , Sweden.,c Department of Clinical Immunology and Transfusion Medicine , County Council of Östergötland , Linköping , Sweden
| | - B Larsson
- d Clinical Chemistry Laboratory , County Council of Östergötland , Sweden
| | - J Wetterö
- a Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine , Faculty of Medicine and Health Sciences, Linköping University , Linköping , Sweden
| | - T Skogh
- a Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine , Faculty of Medicine and Health Sciences, Linköping University , Linköping , Sweden.,e Rheumatology clinic, Heart and Medicine Centre , County Council of Östergötland , Sweden
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15
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Luciani N, Du V, Gazeau F, Richert A, Letourneur D, Le Visage C, Wilhelm C. Successful chondrogenesis within scaffolds, using magnetic stem cell confinement and bioreactor maturation. Acta Biomater 2016; 37:101-10. [PMID: 27063490 DOI: 10.1016/j.actbio.2016.04.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 04/05/2016] [Accepted: 04/06/2016] [Indexed: 01/24/2023]
Abstract
UNLABELLED Tissue engineering strategies, such as cellularized scaffolds approaches, have been explored for cartilage replacement. The challenge, however, remains to produce a cartilaginous tissue incorporating functional chondrocytes and being large and thick enough to be compatible with the replacement of articular defects. Here, we achieved unprecedented cartilage tissue production into a porous polysaccharide scaffold by combining of efficient magnetic condensation of mesenchymal stem cells, and dynamic maturation in a bioreactor. In optimal conditions, all the hallmarks of chondrogenesis were enhanced with a 50-fold increase in collagen II expression compared to negative control, an overexpression of aggrecan and collagen XI, and a very low expression of collagen I and RUNX2. Histological staining showed a large number of cellular aggregates, as well as an increased proteoglycan synthesis by chondrocytes. Interestingly, electron microscopy showed larger chondrocytes and a more abundant extracellular matrix. In addition, the periodicity of the neosynthesized collagen fibers matched that of collagen II. These results represent a major step forward in replacement tissue for cartilage defects. STATEMENT OF SIGNIFICANCE A combination of several innovative technologies (magnetic cell seeding, polysaccharide porous scaffolds, and dynamic maturation in bioreactor) enabled unprecedented successful chondrogenesis within scaffolds.
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Affiliation(s)
- Nathalie Luciani
- Laboratoire Matière et Systèmes Complexes (MSC), UMR 7057 CNRS & University Paris Diderot, Paris F-75205 Cedex 13, France.
| | - Vicard Du
- Laboratoire Matière et Systèmes Complexes (MSC), UMR 7057 CNRS & University Paris Diderot, Paris F-75205 Cedex 13, France
| | - Florence Gazeau
- Laboratoire Matière et Systèmes Complexes (MSC), UMR 7057 CNRS & University Paris Diderot, Paris F-75205 Cedex 13, France
| | - Alain Richert
- Laboratoire Matière et Systèmes Complexes (MSC), UMR 7057 CNRS & University Paris Diderot, Paris F-75205 Cedex 13, France
| | - Didier Letourneur
- Laboratoire de recherche vasculaire translationnelle, INSERM UMR 1148 & University Paris Diderot, Paris, France
| | | | - Claire Wilhelm
- Laboratoire Matière et Systèmes Complexes (MSC), UMR 7057 CNRS & University Paris Diderot, Paris F-75205 Cedex 13, France
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Sandstad J, Stensvold D, Hoff M, Nes BM, Arbo I, Bye A. The effects of high intensity interval training in women with rheumatic disease: a pilot study. Eur J Appl Physiol 2015; 115:2081-9. [PMID: 26013051 DOI: 10.1007/s00421-015-3186-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2014] [Accepted: 05/08/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE Rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA) are inflammatory diseases which involve increased risk of cardiovascular disease (CVD). High intensity interval training (HIIT) is known to be effective in improving cardiovascular health. The aim of this study was to investigate whether 10 weeks of HIIT at 85-95% of HRmax would improve important risk factors of CVD in rheumatic patients, and if these patients would tolerate exercise intensities above today's recommendations. METHODS Seven women with RA and eleven with adult-JIA, 20-50 years, were recruited to this cross-over study. Participants performed HIIT, consisting of 4 × 4 min intervals at 85-95% of HRmax twice a week for 10 weeks on spinning bikes. Maximal oxygen uptake (VO2max), heart rate recovery, blood pressure, body composition, and blood variables were measured before and after the exercise and control period. Disease activity was determined and questionnaire data were collected. RESULTS HIIT resulted in 12.2% increase in VO2max and 2.9% improvement in heart rate recovery (p < 0.05). BMI, body fat, and waist circumference decreased 1.2, 1.0, and 1.6%, respectively, whereas muscle mass increased 0.6% (p < 0.05). A trend toward decreased CRP was detected after HIIT (p = 0.08). No changes were detected in disease activity or pain. CONCLUSION Despite rigorous high intensity exercise, no increase was detected in disease activity or pain, indicating that HIIT was well tolerated by these patients. Furthermore, HIIT had positive effects on several CVD risk factors. In light of this pilot study, HIIT seems like a promising non-pharmacological treatment strategy for patients with RA and adult-JIA.
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Affiliation(s)
- Janne Sandstad
- Department of Circulation and Medical Imaging, Faculty of Medicine, Medical Technology Research Centre, KG Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology (NTNU), P.O. box 8905, 7491, Trondheim, Norway
| | - Dorthe Stensvold
- Department of Circulation and Medical Imaging, Faculty of Medicine, Medical Technology Research Centre, KG Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology (NTNU), P.O. box 8905, 7491, Trondheim, Norway
| | - Mari Hoff
- Department of Rheumatology, St. Olavs Hospital, Trondheim, Norway.,Department of Public Health and General Practice, Norwegian University of Science and Technology, Trondheim, Norway
| | - Bjarne M Nes
- Department of Circulation and Medical Imaging, Faculty of Medicine, Medical Technology Research Centre, KG Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology (NTNU), P.O. box 8905, 7491, Trondheim, Norway
| | - Ingerid Arbo
- Department of Circulation and Medical Imaging, Faculty of Medicine, Medical Technology Research Centre, KG Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology (NTNU), P.O. box 8905, 7491, Trondheim, Norway
| | - Anja Bye
- Department of Circulation and Medical Imaging, Faculty of Medicine, Medical Technology Research Centre, KG Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology (NTNU), P.O. box 8905, 7491, Trondheim, Norway. .,Norwegian Health Association, Oslo, Norway. .,St. Olavs Hospital, Trondheim, Norway.
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17
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Hammad YH, Magid HR, Sobhy MM. Clinical and biochemical study of the comparative efficacy of topical versus oral glucosamine/chondroitin sulfate on osteoarthritis of the knee. EGYPTIAN RHEUMATOLOGIST 2015. [DOI: 10.1016/j.ejr.2014.06.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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18
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Giarratana LS, Marelli BM, Crapanzano C, De Martinis SE, Gala L, Ferraro M, Marelli N, Albisetti W. A randomized double-blind clinical trial on the treatment of knee osteoarthritis: the efficacy of polynucleotides compared to standard hyaluronian viscosupplementation. Knee 2014; 21:661-8. [PMID: 24703391 DOI: 10.1016/j.knee.2014.02.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 01/01/2014] [Accepted: 02/03/2014] [Indexed: 02/02/2023]
Abstract
BACKGROUND This randomized, double-blind, parallel-group clinical trial aims to assess the equivalence of intra-articular polynucleotides compared to standard hyaluronic acid (HA) viscosupplementation in the treatment of knee osteoarthritis (OA). METHODS 75 patients affected by knee OA were assessed for eligibility and 72 were enrolled and randomized to receive either intra-articular polynucleotides (Condrotide-36 patients) or hyaluronic acid (Hyalubrix-36 patients) at the Orthopedic Institute "Gaetano Pini" (Milan). All patients underwent three intra-articular injections of Condrotide or Hyalubrix with an interval of 1week. Participants, care givers, and investigators responsible for outcome assessment were all blinded to group assignment. Primary outcome measurements (KOOS and pain level (1) at rest, (2) at weight-bearing and (3) during physical activity) were evaluated at baseline (T0) and after one (T1), two (T2), six (T6), ten (T10), and 26 (T26)weeks. Secondary measurements included the determination of COMP serum levels at T0, T6 and T26. RESULTS The reduction of pain and the increase of KOOS values from baseline were statistically significant for both treatments; nevertheless, for parameter KOOS "symptoms" the treatment with Condrotide showed significant results already after twoweeks (at T2 p=0.003) while the results obtained with Hyalubrix became significant only after 18 weeks (at T18 p=0.01). No significant adverse events were reported. CONCLUSIONS Condrotide is as effective as Hyalubrix in reducing knee OA symptoms but showed an earlier response on pain reduction and can therefore be considered a valid alternative to the use of HA in the treatment of OA, avoiding the adverse events of NSAIDs and of intra-articular corticosteroids.
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Affiliation(s)
- Laura S Giarratana
- Scuola di Specializzazione in Ortopedia e Traumatologia -Università degli, Studi di Milano, Italy.
| | - Bruno M Marelli
- Direttore Dipartimento Ortopedia e Traumatologia, Istituto Ortopedico Gaetano Pini, Milano, Italy
| | - Calogero Crapanzano
- Direttore U.O.C. Patologia Clinica, Istituto Ortopedico Gaetano Pini, Milano, Italy
| | - Silvia E De Martinis
- Scuola di Specializzazione in Ortopedia e Traumatologia -Università degli, Studi di Milano, Italy
| | - Luca Gala
- Specialista in Ortopedia e Traumatologia, Istituto Ortopedico Gaetano Pini, Milano, Italy
| | - Marcello Ferraro
- Dirigente Medico, Istituto Ortopedico Gaetano Pini, Milano, Italy
| | - Niccolò Marelli
- Facoltà di Medicina e Chirurgia, Università degli Studi di Milano, Italy
| | - Walter Albisetti
- Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, Università degli Studi di Milano, Italy
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Momohara S, Yamanaka H, Holledge MM, Mizumura T, Ikari K, Okada N, Kamatani N, Tomatsu T. Cartilage oligomeric matrix protein in serum and synovial fluid of rheumatoid arthritis: potential use as a marker for joint cartilage damage. Mod Rheumatol 2014. [DOI: 10.3109/s10165-004-0323-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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20
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Andersson MLE, Svensson B, Petersson IF, Hafström I, Albertsson K, Forslind K, Heinegård D, Saxne T. Early increase in serum-COMP is associated with joint damage progression over the first five years in patients with rheumatoid arthritis. BMC Musculoskelet Disord 2013; 14:229. [PMID: 23915292 PMCID: PMC3750296 DOI: 10.1186/1471-2474-14-229] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2013] [Accepted: 07/29/2013] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Currently available biomarkers for the early tissue process leading to joint damage in rheumatoid arthritis are insufficient and lack prognostic accuracy, possibly a result of variable activity of the disease over time. This study represents a novel approach to detect an altered activity of the disease process detected as increasing serum-COMP levels over a short time and whether this would correlate with joint damage progression over the first 5 years of disease. METHODS In all, 349 patients from the Swedish BARFOT early RA study were examined. Serum-COMP was analysed by ELISA at diagnosis and after 3 months. Based on changes in serum-COMP levels, three subgroups of patients were defined: those with unchanged levels (change ≤ 20%) (N=142), decreasing levels (> 20%) (N=173) and increasing levels (> 20%) (N=34). Radiographs of hands and feet were obtained at inclusion, after 1, 2 and 5 years and scored according to Sharp van der Heijde (SHS). Radiographic progression was defined as increase in SHS by ≥5.8. RESULTS The group of patients with increasing COMP levels showed higher median change in total SHS and erosion scores at 1, 2 and 5 year follow-up compared with the groups with stable or decreasing COMP levels. Furthermore, the odds ratio of radiographic progression was 2.8 (95% CI 1.26-6.38) for patients with increasing COMP levels vs. patients with unchanged levels.The group of patients with increasing COMP levels had higher ESR at inclusion but there were no baseline differences between the groups for age, gender, disease duration, disease activity (DAS28), function (HAQ), CRP, nor presence of rheumatoid factor or anti-CCP. Importantly, neither did changes over the 3-month period in DAS28, HAQ, ESR nor CRP differ between the groups and these variables did not correlate to joint damage progression. CONCLUSION Increasing serum-COMP levels between diagnosis and the subsequent 3 months in patients with early RA represents a novel indicator of an activated destructive process in the joint and is a promising tool to identify patients with significant joint damage progression during a 5-year period.
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21
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Karsdal MA, Nielsen MJ, Sand JM, Henriksen K, Genovese F, Bay-Jensen AC, Smith V, Adamkewicz JI, Christiansen C, Leeming DJ. Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure. Assay Drug Dev Technol 2012; 11:70-92. [PMID: 23046407 DOI: 10.1089/adt.2012.474] [Citation(s) in RCA: 196] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Increased attention is paid to the structural components of tissues. These components are mostly collagens and various proteoglycans. Emerging evidence suggests that altered components and noncoded modifications of the matrix may be both initiators and drivers of disease, exemplified by excessive tissue remodeling leading to tissue stiffness, as well as by changes in the signaling potential of both intact matrix and fragments thereof. Although tissue structure until recently was viewed as a simple architecture anchoring cells and proteins, this complex grid may contain essential information enabling the maintenance of the structure and normal functioning of tissue. The aims of this review are to (1) discuss the structural components of the matrix and the relevance of their mutations to the pathology of diseases such as fibrosis and cancer, (2) introduce the possibility that post-translational modifications (PTMs), such as protease cleavage, citrullination, cross-linking, nitrosylation, glycosylation, and isomerization, generated during pathology, may be unique, disease-specific biochemical markers, (3) list and review the range of simple enzyme-linked immunosorbent assays (ELISAs) that have been developed for assessing the extracellular matrix (ECM) and detecting abnormal ECM remodeling, and (4) discuss whether some PTMs are the cause or consequence of disease. New evidence clearly suggests that the ECM at some point in the pathogenesis becomes a driver of disease. These pathological modified ECM proteins may allow insights into complicated pathologies in which the end stage is excessive tissue remodeling, and provide unique and more pathology-specific biochemical markers.
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22
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Hjeltnes G, Hollan I, Førre Ø, Wiik A, Lyberg T, Mikkelsen K, Agewall S. Relations of serum COMP to cardiovascular risk factors and endothelial function in patients with rheumatoid arthritis treated with methotrexate and TNF-α inhibitors. J Rheumatol 2012; 39:1341-7. [PMID: 22660798 DOI: 10.3899/jrheum.111401] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE To examine whether serum level of cartilage oligomeric matrix protein (S-COMP) is related to methotrexate (MTX) or to MTX and tumor necrosis factor-α (TNF-α) combination treatment for rheumatoid arthritis (RA); and to investigate whether S-COMP is related to cardiovascular risk factors including endothelial dysfunction and level of anticitrullinated protein antibodies (ACPA) in patients with RA. METHODS Clinical and laboratory measures, including S-COMP and reactive hyperemic index (RHI), were examined in 55 consecutive patients with RA starting with either MTX (n = 34) or MTX and anti-TNF-α treatment (n = 21) at baseline, and after 6 weeks and 6 months. RESULTS S-COMP was similar in the 2 treatment regimens during followup. We found a positive relationship between S-COMP at baseline and the use of disease-modifying antirheumatic drugs the last year preceding the study (p = 0.001), and a negative relation to current use of systemic glucocorticosteroids (p = 0.044). The nonsignificant change in S-COMP between baseline and the 6-month followup was positively and independently related to change in ACPA level (p = 0.009). There was no significant association between RHI and level of S-COMP at baseline. CONCLUSION The cartilage turnover marker S-COMP did not change significantly after 6 months' treatment with MTX with or without a TNF-α inhibitor in patients with RA. The positive association between S-COMP and ACPA suggests that these factors might interact, and could both be contributors to an unknown link between inflammation and cartilage destruction in patients with RA. S-COMP was not related to endothelial function in patients with RA, or to other cardiovascular risk factors studied. Clinical Trials registration number NCT00902005.
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Affiliation(s)
- Gunnbjørg Hjeltnes
- Lillehammer Hospital for Rheumatic Diseases, M. Grundtvigsv. 6, 2609 Lillehammer, Norway.
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Niki Y, Takeuchi T, Nakayama M, Nagasawa H, Kurasawa T, Yamada H, Toyama Y, Miyamoto T. Clinical significance of cartilage biomarkers for monitoring structural joint damage in rheumatoid arthritis patients treated with anti-TNF therapy. PLoS One 2012; 7:e37447. [PMID: 22629396 PMCID: PMC3357428 DOI: 10.1371/journal.pone.0037447] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Accepted: 04/19/2012] [Indexed: 12/03/2022] Open
Abstract
Purpose With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage. Methods Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated. Results Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation. Conclusion The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3.
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Affiliation(s)
- Yasuo Niki
- Department of Orthopaedic Surgery, School of Medicine, Keio University, Tokyo, Japan.
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24
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Prajapati R, Plant D, Barton A. Genetic and genomic predictors of anti-TNF response. Pharmacogenomics 2012; 12:1571-85. [PMID: 22044414 DOI: 10.2217/pgs.11.114] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The introduction of anti-TNF therapy has dramatically improved the outlook for patients suffering from a number of inflammatory conditions including rheumatoid arthritis and inflammatory bowel disease. Despite this, a substantial proportion of patients (approximately 30-40%) fail to respond to these potentially toxic and expensive therapies. Treatment response is likely to be multifactorial; however, variation in genes or their expression may identify those most likely to respond. By targeted testing of variants within candidate genes, potential predictors of anti-TNF response have been reported; however, very few markers have replicated consistently between studies. Emerging genome-wide association studies suggest that there may be a number of genes with modest effects on treatment response rather than a few genes of large effect. Other potential serum biomarkers of response have also been explored including cytokines and autoantibodies, with antibodies developing to the anti-TNF drugs themselves being correlated with treatment failure.
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Affiliation(s)
- Rita Prajapati
- Arthritis Research UK Epidemiology Unit, Manchester Academy of Health Sciences, University of Manchester, Manchester, UK
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25
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Happonen KE, Saxne T, Geborek P, Andersson M, Bengtsson AA, Hesselstrand R, Heinegård D, Blom AM. Serum COMP-C3b complexes in rheumatic diseases and relation to anti-TNF-α treatment. Arthritis Res Ther 2012; 14:R15. [PMID: 22264230 PMCID: PMC3392805 DOI: 10.1186/ar3694] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Revised: 12/21/2011] [Accepted: 01/20/2012] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Cartilage oligomeric matrix protein (COMP) is found at elevated concentrations in sera of patients with joint diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). We recently showed that COMP activates complement via the alternative pathway and that COMP-C3b complexes are present in sera of RA patients, but not in healthy controls. We now set out to elaborate on the information provided by this marker in a variety of diseases and larger patient cohorts. METHODS COMP-C3b levels in sera were measured by using an enzyme-linked immunosorbent assay (ELISA) capturing COMP and detecting C3b. Serum COMP was measured by using ELISA. RESULTS COMP-C3b levels were significantly elevated in patients with RA as well as in systemic lupus erythematosus (SLE), compared with healthy controls. SLE patients with arthritis had significantly higher COMP-C3b levels than did those without. COMP-C3b was furthermore elevated in patients with ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, systemic sclerosis, and OA. COMP-C3b did not correlate with COMP in any of the patient groups. COMP-C3b correlated with disease activity in RA, but not in other diseases. COMP-C3b levels in RA patients decreased on treatment with tumor necrosis factor (TNF)-α inhibitors, whereas the levels increased in patients with AS or PsA. The changes of COMP-C3b did not parallel the changes of C-reactive protein (CRP). CONCLUSIONS COMP-C3b levels are elevated in several rheumatologic diseases and correlate with inflammatory measures in RA. COMP-C3b levels in RA decrease during TNF-α inhibition differently from those of CRP, suggesting that formation of COMP-C3b relates to disease features not reflected by general inflammation measures.
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Affiliation(s)
- Kaisa E Happonen
- Department of Laboratory Medicine Malmö, Section of Medical Protein Chemistry, Lund University, Wallenberg Laboratory floor 4, SE-205 02 Malmö, Sweden
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Cartilage Oligomeric Matrix Protein (COMP) in systemic sclerosis (SSc): Role in disease severity and subclinical rheumatoid arthritis overlap. Joint Bone Spine 2012; 79:51-6. [DOI: 10.1016/j.jbspin.2011.02.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2010] [Accepted: 02/23/2011] [Indexed: 11/20/2022]
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Kalchishkova N, Fürst CM, Heinegård D, Blom AM. NC4 Domain of cartilage-specific collagen IX inhibits complement directly due to attenuation of membrane attack formation and indirectly through binding and enhancing activity of complement inhibitors C4B-binding protein and factor H. J Biol Chem 2011; 286:27915-26. [PMID: 21659506 DOI: 10.1074/jbc.m111.242834] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Collagen IX containing the N-terminal noncollagenous domain 4 (NC4) is unique to cartilage and a member of the family of fibril-associated collagens with both collagenous and noncollagenous domains. Collagen IX is located at the surface of fibrils formed by collagen II and a minor proportion of collagen XI, playing roles in tissue stability and integrity. The NC4 domain projects out from the fibril surface and provides sites for interaction with other matrix components such as cartilage oligomeric matrix protein, matrilins, fibromodulin, and osteoadherin. Fragmentation of collagen IX and loss of the NC4 domain are early events in cartilage degradation in joint diseases that precedes major damage of collagen II fibrils. Our results demonstrate that NC4 can function as a novel inhibitor of the complement system able to bind C4, C3, and C9 and to directly inhibit C9 polymerization and assembly of the lytic membrane attack complex. NC4 also binds the complement inhibitors C4b-binding protein and factor H and enhances their cofactor activity in degradation of activated complement components C4b and C3b. NC4 interactions with fibromodulin and osteoadherin inhibited binding to C1q and complement activation by these proteins. Taken together, our results suggest that collagen IX and its interactions with matrix components are important parts of a machinery that protects the cartilage from complement activation and chronic inflammation seen in diseases like rheumatoid arthritis.
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Affiliation(s)
- Nikolina Kalchishkova
- Department of Laboratory Medicine, Section of Medical Protein Chemistry, Lund University, S-205 02 Malmö, Sweden
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Karsdal MA, Woodworth T, Henriksen K, Maksymowych WP, Genant H, Vergnaud P, Christiansen C, Schubert T, Qvist P, Schett G, Platt A, Bay-Jensen AC. Biochemical markers of ongoing joint damage in rheumatoid arthritis--current and future applications, limitations and opportunities. Arthritis Res Ther 2011; 13:215. [PMID: 21539724 PMCID: PMC3132026 DOI: 10.1186/ar3280] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease associated with potentially debilitating joint inflammation, as well as altered skeletal bone metabolism and co-morbid conditions. Early diagnosis and aggressive treatment to control disease activity offers the highest likelihood of preserving function and preventing disability. Joint inflammation is characterized by synovitis, osteitis, and/or peri-articular osteopenia, often accompanied by development of subchondral bone erosions, as well as progressive joint space narrowing. Biochemical markers of joint cartilage and bone degradation may enable timely detection and assessment of ongoing joint damage, and their use in facilitating treatment strategies is under investigation. Early detection of joint damage may be assisted by the characterization of biochemical markers that identify patients whose joint damage is progressing rapidly and who are thus most in need of aggressive treatment, and that, alone or in combination, identify those individuals who are likely to respond best to a potential treatment, both in terms of limiting joint damage and relieving symptoms. The aims of this review are to describe currently available biochemical markers of joint metabolism in relation to the pathobiology of joint damage and systemic bone loss in RA; to assess the limitations of, and need for additional, novel biochemical markers in RA and other rheumatic diseases, and the strategies used for assay development; and to examine the feasibility of advancement of personalized health care using biochemical markers to select therapeutic agents to which a patient is most likely to respond.
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Affiliation(s)
- Morten A Karsdal
- Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark
- Southern University of Denmark (SDU), Campusvej 55DK-5230 Odense M Denmark
| | - Thasia Woodworth
- Leading Edge Clinical Research LLC, 3901 SE St Lucie Blvd unit 20, Stuart, Florida 34997, USA
| | - Kim Henriksen
- Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark
| | - Walter P Maksymowych
- University of Alberta, 562 Heritage Medical Research Building, Edmonton, AB T6G 2S2, Canada
| | | | | | | | | | - Per Qvist
- Nordic Bioscience, Herlev Hovedgade 207, DK-2730 Herlev, Denmark
| | - Georg Schett
- University of Erlangen-Nurnberg Department of Internal Medicine, Krankenhausstraße 12, 91054 Erlangen, Germany
| | - Adam Platt
- Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, UK
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Kawashiri SY, Kawakami A, Ueki Y, Imazato T, Iwamoto N, Fujikawa K, Aramaki T, Tamai M, Nakamura H, Origuchi T, Ida H, Eguchi K. Decrement of serum cartilage oligomeric matrix protein (COMP) in rheumatoid arthritis (RA) patients achieving remission after 6 months of etanercept treatment: Comparison with CRP, IgM-RF, MMP-3 and anti-CCP Ab. Joint Bone Spine 2010; 77:418-20. [DOI: 10.1016/j.jbspin.2010.01.016] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Accepted: 01/25/2010] [Indexed: 12/01/2022]
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Bender AL, da Silveira IG, von Mühlen CA, Staub HL. High specificity but low sensitivity of the cartilage oligomeric matrix protein (COMP) test in rheumatoid arthritis and osteoarthritis. Clin Chem Lab Med 2010; 48:569-70. [PMID: 20148721 DOI: 10.1515/cclm.2010.081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Wu T, Sajitharan D, Mohan C. Biomarkers of rheumatoid arthritis: recent progress. ACTA ACUST UNITED AC 2010; 4:293-305. [DOI: 10.1517/17530059.2010.492828] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Nam J, Villeneuve E, Emery P. The role of biomarkers in the management of patients with rheumatoid arthritis. Curr Rheumatol Rep 2009; 11:371-7. [PMID: 19772833 DOI: 10.1007/s11926-009-0053-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
In recent years, patient outcomes have improved dramatically with the availability of effective treatments for the management of rheumatoid arthritis (RA). RA, however, is a heterogeneous disease with variable disease progression and treatment response. Whereas some patients respond to a single disease-modifying antirheumatic drug, others require more intensive treatment strategies. Assessing disease severity at diagnosis and monitoring disease activity on an individual level would be a more accurate way of tailoring therapy, ensuring optimal treatment for those at greatest risk of disease progression, long-term disability, and joint damage without unnecessary overtreatment. Assessment of disease activity and severity is currently based on a combination of clinical and laboratory parameters that aid treatment decisions. Use of biomarkers may provide a more accurate means of objectively assessing the disease. This article reviews the role of biomarkers in the management of RA.
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Affiliation(s)
- Jackie Nam
- Academic Unit of Musculoskeletal Diseases, 2nd Floor Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, United Kingdom
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Tampoia M, Brescia V, Falappone P, Zucano A, Scioscia C, Fontana A, Iannone F, Di Serio F, Lapadula G. Response of Cartilage Oligomeric Matrix Protein to Monoclonal Antibody Drugs in Patients with Rheumatoid Arthritis. Lab Med 2009. [DOI: 10.1309/lmv894xjrqejmkab] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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BJØRNHART BIRGITTE, JUUL ANDERS, NIELSEN SUSAN, ZAK MAREK, SVENNINGSEN PERNILLE, MÜLLER KLAUS. Cartilage Oligomeric Matrix Protein in Patients with Juvenile Idiopathic Arthritis: Relation to Growth and Disease Activity. J Rheumatol 2009; 36:1749-54. [DOI: 10.3899/jrheum.080942] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objective.Cartilage oligomeric matrix protein (COMP) has been identified as a prognostic marker of progressive joint destruction in rheumatoid arthritis. In this population based study we evaluated associations between plasma concentrations of COMP, disease activity, and growth velocity in patients with recent-onset juvenile idiopathic arthritis (JIA). COMP levels in JIA and healthy children were compared with those in healthy adults. Plasma levels of insulin-like growth factor I (IGF-1), which has been associated with COMP expression and growth velocity, were studied in parallel.Methods.87 patients with JIA entered the study, including oligoarticular JIA (n = 34), enthesitis-related arthritis (n = 8), polyarticular rheumatoid factor (RF)-positive JIA (n = 2), polyarticular RF-negative JIA (n = 27), systemic JIA (n = 6), and undifferentiated JIA (n = 10). Plasma levels of COMP were measured by ELISA and IGF-1 by a radioimmunoassay.Results.Significantly higher COMP levels [mean 18.9 U/l (95% CI 17.3–20.5)] were found in healthy children compared with healthy adults [mean 10.7 U/l (95% CI 9.4–12.1)] (p < 0.0001). COMP levels in the JIA patients [mean 13.5 U/l (95% CI 12.4–14.7)] were significantly reduced compared to healthy children (p < 0.0001), and correlated negatively with C-reactive protein (CRP; r = −0.29, p = 0.01) and thrombocyte count (r = −0.28, p = 0.02). COMP levels in the JIA patients correlated positively with growth velocity (cm/yr) (r = 0.38, p = 0.0003) and growth velocity (SDS) (r = 0.29, p = 0.007).Conclusion.We found reduced COMP levels in children with JIA compared with healthy children. COMP levels in JIA correlated negatively with inflammatory activity as evaluated by CRP and the thrombocyte counts, and were associated with reduced growth rate.
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da Mota LMH, dos Santos Neto LL, de Carvalho JF. Autoantibodies and other serological markers in rheumatoid arthritis: predictors of disease activity? Clin Rheumatol 2009; 28:1127-34. [DOI: 10.1007/s10067-009-1223-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2009] [Accepted: 06/17/2009] [Indexed: 01/06/2023]
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Karsdal M, Henriksen K, Leeming D, Mitchell P, Duffin K, Barascuk N, Klickstein L, Aggarwal P, Nemirovskiy O, Byrjalsen I, Qvist P, Bay-Jensen A, Dam E, Madsen S, Christiansen C. Biochemical markers and the FDA Critical Path: How biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development. Biomarkers 2009; 14:181-202. [DOI: 10.1080/13547500902777608] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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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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Sumer EU, Schaller S, Sondergaard BC, Tankó LB, Qvist P. Application of biomarkers in the clinical development of new drugs for chondroprotection in destructive joint diseases: a review. Biomarkers 2008; 11:485-506. [PMID: 17056470 DOI: 10.1080/13547500600886115] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Emerging evidence supports the concept that biochemical markers are clinically useful non-invasive diagnostic tools for the monitoring of changes in cartilage turnover in patients with destructive joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Epidemiological studies demonstrated that measurements of different degradation products of proteins in the extracellular matrix of hyaline cartilage in urine or serum samples are (1) increased in OA or RA patients compared with healthy individuals, (2) correlate with disease activity, and (3) are predictive for the rate of changes in radiographic measures of cartilage loss. The present review provides an updated list of available biomarkers and summarize the research data arguing for their clinical utility. In addition, it addresses the question whether or not the monitoring of biomarkers during different treatment modalities could be a useful approach to characterize the chondro-protective effects of approved and candidate drugs. Finally, it briefly reviews the in vitro/ex vivo experimental settings - isolated chondrocyte cultures and articular cartilage explants - that can assist in the verification of novel markers, but also studies assessing direct effects of drug candidates on chondrocytes. Collectively, biomarkers may acquire a function as established efficacy parameters in the clinical development of novel chondro-protective agents.
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Affiliation(s)
- E U Sumer
- Nordic Bioscience A/S, Herlev, Denmark.
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Abstract
Human serum contains two related isoforms of TRACP: TRACP 5a and TRACP 5b. Serum TRACP 5a protein is increased in about one third of rheumatoid arthritis (RA) sera. This study was undertaken to examine the significance of serum TRACP isoforms 5a and 5b as disease markers of inflammation and bone destruction in RA. One hundred eighteen patients were recruited including 50 with RA (25 with nodules), 26 with osteoarthritis (OA), and 42 with other rheumatic diseases. Twenty-six healthy adults served as controls. Serum TRACP 5a activity, TRACP 5a protein, and TRACP 5b activity were determined by in-house immunoassays. C-reactive protein (CRP) was determined by in-house immunoassay using commercial antibodies and CRP. Other commercial markers included bone-specific alkaline phosphatase (BALP), C-telopeptides of type-I collagen (ICTP), cartilage glycoprotein-39 (YKL-40), and IgM rheumatoid factors (IgM-RF). Mean TRACP 5a protein was significantly elevated only in RA compared with healthy controls and other disease groups. TRACP 5a protein correlated significantly only with IgM-RF in RA. Among RA patients, mean TRACP 5a protein and IgM RF were significantly higher in nodule formers. In contrast, TRACP 5b activity was slightly elevated in RA and correlated with BALP, ICTP, and YKL-40 but not with IgM-RF or CRP. Mean TRACP 5b activity was no different in RA patients with or without nodules. TRACP isoforms could be useful disease markers in RA; TRACP 5a protein may be a measure of systemic inflammatory macrophage burden and disease severity. TRACP 5b activity is a marker for osteoclast number and perhaps local or systemic bone destruction.
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Bajpai M, Chopra P, Dastidar SG, Ray A. Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis. Expert Opin Investig Drugs 2008; 17:641-59. [PMID: 18447591 DOI: 10.1517/13543784.17.5.641] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND In the last few years, significant progress has been made in understanding the pathogenic mechanisms and in defining the role of relevant cells and molecules in the pathophysiology of rheumatoid arthritis (RA). Various therapies, both biological (anti-TNF, anti-interleukins [e.g., IL-1]) and small molecule inhibitors have been explored for the treatment of RA. OBJECTIVE To date, no single signaling pathway inhibitor as wide acting as the corticosteroids, is known. However, treatment with corticosteroids is also associated with allied side effects. Despite a lot of efforts in the category of small molecule inhibitors, no inhibitor is available to deal with RA at both fronts (inflammation and tissue damage), without causing immense side effects. METHOD This present review explores the role of spleen tyrosine kinase (Syk) in the pathogenesis of RA and also discusses how it may meet the present day therapeutic requirements for the treatment of RA. This review gives an in-depth discussion on the role of Syk signaling in RA, the possibilities of using Syk as a target and also discusses the possible side effects that could be associated with its inhibition. CONCLUSION We propose Syk inhibition as a potential therapeutic approach for the treatment of RA.
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Affiliation(s)
- Malini Bajpai
- Department of Pharmacology, New Drug Discovery Research, Ranbaxy Research Laboratories, Plot No-20, Sector-18, Gurgaon-122001-Haryana, India.
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Kloppenburg M, Stamm T, Watt I, Kainberger F, Cawston TE, Birrell FN, Petersson IF, Saxne T, Kvien TK, Slatkowsky-Christensen B, Dougados M, Gossec L, Breedveld FC, Smolen JS. Research in hand osteoarthritis: time for reappraisal and demand for new strategies. An opinion paper. Ann Rheum Dis 2007; 66:1157-61. [PMID: 17360780 PMCID: PMC1955144 DOI: 10.1136/ard.2007.070813] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2007] [Indexed: 01/09/2023]
Abstract
BACKGROUND Osteoarthritis of the hands is a prevalent musculoskeletal disease with a considerable effect on patients' lives, but knowledge and research results in the field of hand osteoarthritis are limited. Therefore, the Disease Characteristics in Hand OA (DICHOA) initiative was founded in early 2005 with the aim of addressing key issues and facilitating research into hand osteoarthritis. OBJECTIVE To review and discuss current knowledge on hand osteoarthritis with regard to aetiopathogenesis, diagnostic criteria, biomarkers and clinical outcome measures. METHODS Recommendations were made based on a literature review. RESULTS Outcomes of hand osteoarthritis should be explored, including patient perspective on the separate components of disease activity, damage and functioning. All imaging techniques should be cross-validated for hand osteoarthritis with clinical status, including disease activity, function and performance, biomarkers and long-term outcome. New imaging modalities are available and need scoring systems and validation. The role of biomarkers in hand osteoarthritis has to be defined. CONCLUSION Future research in hand osteoarthritis is warranted.
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Affiliation(s)
- Margreet Kloppenburg
- Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
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Morozzi G, Fabbroni M, Bellisai F, Pucci G, Galeazzi M. Cartilage Oligomeric Matrix Protein Level in Rheumatic Diseases: Potential Use as a Marker for Measuring Articular Cartilage Damage and/or the Therapeutic Efficacy of Treatments. Ann N Y Acad Sci 2007; 1108:398-407. [PMID: 17894003 DOI: 10.1196/annals.1422.041] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cartilage oligomeric matrix protein (COMP) is a tissue-specific noncollagenous protein that was first detected in the serum and the synovial fluid of patients suffering from rheumatic disorders, such as rheumatoid arthritis, reactive arthritis, juvenile chronic arthritis, and osteoarthritis. In this review, the authors consider serum COMP levels in different diseases and discuss their study of patients with rheumatoid arthritis treated with anti-TNF-alpha, to evaluate whether COMP is able to predict a rapid and sustained clinical response to these drugs. They observe that patients with high COMP levels have a lower ACR 70 response independently of the state of systemic inflammation, and conclude that COMP seems to have a pathogenetic role that is independent of the mechanisms regulating inflammatory processes.
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Affiliation(s)
- Gabriella Morozzi
- Department of Clinical Medicine and Immunology, Rheumatology Section, University of Siena, Siena, Italy.
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Pine PR, Chang B, Schoettler N, Banquerigo ML, Wang S, Lau A, Zhao F, Grossbard EB, Payan DG, Brahn E. Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin Immunol 2007; 124:244-57. [PMID: 17537677 DOI: 10.1016/j.clim.2007.03.543] [Citation(s) in RCA: 171] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2007] [Revised: 03/08/2007] [Accepted: 03/09/2007] [Indexed: 02/03/2023]
Abstract
Spleen tyrosine kinase (Syk), a key mediator of immunoreceptor signaling in inflammatory cells, is essential for immune complex-mediated signal transduction initiated by activated receptors for immunoglobulin G. In collagen-induced arthritis, R788/R406, a novel and potent small molecule Syk inhibitor suppressed clinical arthritis, bone erosions, pannus formation, and synovitis. Serum anti-collagen type II antibody levels were unaltered, while the half-life of exogenous antibody was extended when co-administered with R406. Expression of the targeted kinase (Syk) in synovial tissue correlated with the joint level of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting a sensitive and reliable biomarker for R406 activity. These results highlight the role of activating Fcgamma receptors in inflammatory synovitis and suggest that interruption of the signaling cascade with a novel Syk inhibitor may be a useful addition to immunosuppressive disease-modifying anti-rheumatic drugs currently used in the treatment of human autoimmune diseases such as rheumatoid arthritis.
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Affiliation(s)
- Polly R Pine
- Rigel Pharmaceuticals, Inc., 1180 Veterans Blvd., San Francisco, CA 94080, USA
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Hannig G, Bernier SG, Hoyt JG, Doyle B, Clark E, Karp RM, Lorusso J, Westlin WF. Suppression of inflammation and structural damage in experimental arthritis through molecular targeted therapy with PPI-2458. ACTA ACUST UNITED AC 2007; 56:850-60. [PMID: 17328059 DOI: 10.1002/art.22402] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To determine the disease-modifying activity and mechanism of action of the orally available methionine aminopeptidase type 2 inhibitor, [(1R)-1-carbamoyl-2-methyl-propyl]-carbamic acid-(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro [2.5] oct-6-yl ester (PPI-2458), in a rat model of peptidoglycan-polysaccharide (PG-PS)-induced arthritis. METHODS Arthritis was induced in rats by administration of PG-PS, causing tarsal joint swelling and histopathologic changes characteristic of rheumatoid arthritis (RA). PPI-2458, a potent irreversible methionine aminopeptidase type 2 inhibitor, was administered orally every other day at 1, 5, or 10 mg/kg. RESULTS In an in vitro osteoclastogenesis model, PPI-2458 potently inhibited osteoclast differentiation and bone resorption. In the rat PG-PS arthritis model, PPI-2458 afforded significant protection against established disease after therapeutic dosing. This in vivo activity of PPI-2458 was linked to the inhibition of methionine aminopeptidase type 2. Histopathologic assessment of affected joints showed improvement in processes of inflammation, bone resorption, and cartilage erosion, associated with significant improvement in all clinical indices. The protective effects of PPI-2458 against bone destruction in vivo, including the structural preservation of affected hind joints, correlated with improvements in bone histomorphometric markers, as determined by microfocal computed tomography and a significant decrease in systemic C-telopeptide of type I collagen, suggesting decreased osteoclast activity in vivo. Moreover, PPI-2458 prevented cartilage erosion as shown by a significant decrease in systemic cartilage oligomeric matrix protein. CONCLUSION The findings of this study suggest that PPI-2458 exerts disease-modifying activity in experimental arthritis through its direct inhibition of several pathophysiologic processes of this disease. These results provide a rationale for assessing the potential of PPI-2458 as a novel RA therapy.
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Affiliation(s)
- Gerhard Hannig
- Praecis Pharmaceuticals, Waltham, Massachusetts 02451, USA.
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Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, Shinomura Y, Imai K. [Evidence of cartilaginous benefit of treatment with infliximab in rheumatoid arthritis using measurement of serum COMP]. NIHON RINSHO MEN'EKI GAKKAI KAISHI = JAPANESE JOURNAL OF CLINICAL IMMUNOLOGY 2007; 30:41-7. [PMID: 17332704 DOI: 10.2177/jsci.30.41] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Recently, it has become possible to measure the concentration of serum cartilage oligomeric matrix protein (COMP) in various arthritis, and it is expected to be a novel biomarker indicative of cartilage destruction. In this study, we evaluated the diagnostic effectiveness of serum COMP in rheumatic diseases and analyzed the inhibition of cartilage destruction in patients with rheumatoid arthritis who were prescribed with infliximab (IFX) for one year. The changes in the concentration of serum COMP and the joint narrow space of Sharp score (Delta Sharp-JNS) were evaluated. The level of serum COMP decreased from 23.04+/-7.14 U/l to 8.69+/-2.89 U/l (p<0.005) and improved Delta Sharp-JNS (-0.50+/-6.38 points). We believed that these results were influenced by the effects of methotrexate (MTX) that was prescribed together with IFX, and we analyzed the group that was administered only MTX therapy as a reference. However, the serum COMP concentration and Sharp-JNS in the MTX group did not decrease. The serological and radiological results revealed that IFX inhibited cartilage destruction, and it is possible that serum COMP is one of the novel biomarkers in RA patients treated with anti-tumor necrosis factor-alpha antibody therapy.
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Affiliation(s)
- Motohisa Yamamoto
- First Department of Internal Medicine, Sapporo Medical University School of Medicine
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Morozzi G, Fabbroni M, Bellisai F, Cucini S, Simpatico A, Galeazzi M. Low serum level of COMP, a cartilage turnover marker, predicts rapid and high ACR70 response to adalimumab therapy in rheumatoid arthritis. Clin Rheumatol 2007; 26:1335-8. [PMID: 17285224 DOI: 10.1007/s10067-006-0520-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2006] [Revised: 12/15/2006] [Accepted: 12/19/2006] [Indexed: 01/18/2023]
Abstract
The aim of this study was to evaluate serum biomarkers, used in clinical routine, to predict the American College of Rheumatology (ACR) response to long-term anti-TNF alpha treatment (adalimumab). Sera from 29 consecutive rheumatoid arthritis patients were analysed for anti-cyclic citrullinated peptide (anti-CCP), cartilage oligomeric matrix protein (COMP) and IgM and IgA RFs (class-specific rheumatoid factors) at the start of treatment with adalimumab and after 3, 6 and 12 months. The response to the therapy was evaluated by ACR 20, 50, 70 and by DAS 28 scores. The mean serum COMP level of the population did not change after treatment. However, patients with low serum COMP levels (<10 U/l) at baseline showed a significant (p<0.02) higher ACR70 response (>50%) within 3 months, and also at 6 months, than patients with higher COMP values (ACR70<20%). This was also reflected by significantly higher decrease in DAS score at 3 (p<0.02) and 6 months (p<0.01) treatments. The IgM RF titre decreased significantly (p=0.02) after the therapy, but the percentage of serum positivity for anti-CCP and IgA/IgM RF did not change. No significant correlation was shown between serum COMP levels and C-reactive protein/erythrocyte sedimentation rate during the follow-up. Neither were any correlations shown between ACR/DAS 28 scores and anti-CCP, Ig M/IgA RFs. Our data indicate that low (<10 U/l) serum COMP before starting anti-TNF alpha treatment predicts a rapid (within 3 months) and high ACR70 response compared to RA patients with higher COMP values. This might reflect different mechanisms in the cartilage process in the RA disease at that time of treatment with different therapeutic sensitivity to anti-TNF alpha treatment.
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Affiliation(s)
- G Morozzi
- Dipartimento di Medicina Clinica e Scienze Immunologiche-Sezione di Reumatologia, Università di Siena-Policlinico Le Scotte, Viale Bracci, 53100, Siena, Italy.
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Andersson MLE, Thorstensson CA, Roos EM, Petersson IF, Heinegård D, Saxne T. Serum levels of cartilage oligomeric matrix protein (COMP) increase temporarily after physical exercise in patients with knee osteoarthritis. BMC Musculoskelet Disord 2006; 7:98. [PMID: 17156423 PMCID: PMC1712338 DOI: 10.1186/1471-2474-7-98] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2006] [Accepted: 12/07/2006] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND COMP (Cartilage oligomeric matrix protein) is a matrix protein, which is currently studied as a potential serum marker for cartilage processes in osteoarthritis (OA). The influence of physical exercise on serum COMP is not fully elucidated. The objective of the present study was to monitor serum levels of COMP during a randomised controlled trial of physical exercise vs. standardised rest in individuals with symptomatic and radiographic knee OA. METHODS Blood samples were collected from 58 individuals at predefined time points before and after exercise or rest, one training group and one control group. The physical exercise consisted of a one-hour supervised session twice a week and daily home exercises. In a second supplementary study 7 individuals were subjected to the same exercise program and sampling of blood was performed at fixed intervals before, immediately after, 30 and 60 minutes after the exercise session and then with 60 minutes interval for another five hours after exercise to monitor the short-term changes of serum COMP. COMP was quantified with a sandwich-ELISA (AnaMar Medical, Lund, Sweden). RESULTS Before exercise or rest no significant differences in COMP levels were seen between the groups. After 60 minutes exercise serum COMP levels increased (p < 0.001). After 60 minutes of rest the serum levels decreased (p = 0.003). Median serum COMP values in samples obtained prior to exercise or rest at baseline and after 24 weeks did not change between start and end of the study. In the second study serum COMP was increased immediately after exercise (p = 0.018) and had decreased to baseline levels after 30 minutes. CONCLUSION Serum COMP levels increased during exercise in individuals with knee OA, whereas levels decreased during rest. The increased serum COMP levels were normalized 30 minutes after exercise session, therefore we suggest that samples of blood for analysis of serum COMP should be drawn after at least 30 minutes rest in a seated position. No increase was seen after a six-week exercise program indicating that any effect of individualized supervised exercise on cartilage turnover is transient.
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Affiliation(s)
- Maria LE Andersson
- Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden
- Department of Rheumatology, Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Carina A Thorstensson
- Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden
- Department of Rheumatology, Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Ewa M Roos
- Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden
- Department of Orthopaedics, Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Ingemar F Petersson
- Spenshult Hospital for Rheumatic Diseases, Halmstad, Sweden
- Department of Orthopaedics, Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Dick Heinegård
- Department of Experimental Medical Science, Section for Cell and Matrix Biology, Lund University, Sweden
| | - Tore Saxne
- Department of Rheumatology, Clinical Sciences Lund, Lund University, Lund, Sweden
- Department of Experimental Medical Science, Section for Cell and Matrix Biology, Lund University, Sweden
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Schopf L, Savinainen A, Anderson K, Kujawa J, DuPont M, Silva M, Siebert E, Chandra S, Morgan J, Gangurde P, Wen D, Lane J, Xu Y, Hepperle M, Harriman G, Ocain T, Jaffee B. IKKbeta inhibition protects against bone and cartilage destruction in a rat model of rheumatoid arthritis. ACTA ACUST UNITED AC 2006; 54:3163-73. [PMID: 17009244 DOI: 10.1002/art.22081] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE The IKK complex regulates NF-kappaB activation, an important pathway implicated in the rheumatoid arthritis (RA) disease process. This study was undertaken to assess the efficacy of N-(6-chloro-7-methoxy-9H-beta-carbolin-8-yl)-2-methylnicotinamide (ML120B), a potent and selective small molecule inhibitor of IKKbeta. METHODS Polyarthritis was induced in rats by injection of Freund's complete adjuvant into the hind footpad. ML120B was administered orally twice daily, either prophylactically or therapeutically. Paw volumes and body weights were measured every 2-3 days throughout the study. We assessed bone erosions by several methods: histologic evaluation, quantitative micro-computed tomography (micro-CT) imaging analysis, and measurement of type I collagen fragments in the serum. Quantitative polymerase chain reaction was used to evaluate expression of messenger RNA for genes related to inflammation and to bone and cartilage integrity. RESULTS Oral administration of ML120B inhibited paw swelling in a dose-dependent manner (median effective dosage 12 mg/kg twice daily) and offered significant protection against arthritis-induced weight loss as well as cartilage and bone erosion. We were able to directly demonstrate that NF-kappaB activity in arthritic joints was reduced after ML120B administration. Also, we observed that down-regulation of the NF-kappaB pathway via IKKbeta inhibition dampened the chronic inflammatory process associated with rat adjuvant-induced arthritis. CONCLUSION The results of the present study suggest that IKKbeta inhibition is an effective therapeutic approach to treat both the inflammation and the bone/cartilage destruction observed in RA. Methods for the determination of serum markers for bone and cartilage destruction, as well as micro-CT analysis, may aid in predicting and evaluating the therapeutic efficacy of IKKbeta inhibition therapy in humans.
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Affiliation(s)
- Lisa Schopf
- Millennium Pharmaceuticals, Cambridge, Massachusetts, USA.
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Andersson MLE, Petersson IF, Karlsson KE, Jonsson EN, Månsson B, Heinegård D, Saxne T. Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis. Ann Rheum Dis 2006; 65:1490-4. [PMID: 16707535 PMCID: PMC1798358 DOI: 10.1136/ard.2005.051292] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/01/2006] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To monitor changes in serum concentrations of cartilage oligomeric matrix protein (COMP) during a 24-h period to determine any diurnal variation, and to estimate the half life of COMP in the circulation in patients with symptomatic knee osteoarthritis and in those with rheumatoid arthritis. METHODS Serum samples were drawn every 4 h (7 samples/patient over 24 h) in 10 patients with knee osteoarthritis and 14 patients with rheumatoid arthritis. Osteoarthritis was defined radiographically and clinically (American College of Rheumatology (ACR) criteria) and rheumatoid arthritis according to the 1987 ACR criteria. Serum COMP was measured by sandwich ELISA. A statistical model for the diurnal variation in the COMP levels was developed using the computer program NONMEM. RESULTS No considerable changes in COMP levels were observed during the day between 08:00 and 21:00 in either group. A significant decrease in serum COMP was apparent during bed rest at night, reaching the lowest levels between 04:00 and 05:00 (p<0.03 or better v all other time points) in patients with osteoarthritis and in those with rheumatoid arthritis. From the rate of decreasing serum COMP levels, a putative half life of COMP in the circulation was estimated to be 7.4 h. CONCLUSION During normal daytime activities, serum COMP levels are constant. The decrease during the night indicates a rapid elimination of COMP once it has reached the circulation. The stable COMP levels during the day suggest that it is not necessary to further standardise the time of serum sampling in clinical practice.
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Affiliation(s)
- M L E Andersson
- Spenshult's Hospital for Rheumatic Diseases, Halmstad, Sweden.
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Medicherla S, Ma JY, Mangadu R, Jiang Y, Zhao JJ, Almirez R, Kerr I, Stebbins EG, O'Young G, Kapoun AM, Luedtke G, Chakravarty S, Dugar S, Genant HK, Protter AA. A Selective p38α Mitogen-Activated Protein Kinase Inhibitor Reverses Cartilage and Bone Destruction in Mice with Collagen-Induced Arthritis. J Pharmacol Exp Ther 2006; 318:132-41. [PMID: 16597712 DOI: 10.1124/jpet.105.098020] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Destruction of cartilage and bone is a poorly managed hallmark of human rheumatoid arthritis (RA). p38 Mitogen-activated protein kinase (MAPK) has been shown to regulate key proinflammatory pathways in RA, including tumor necrosis factor alpha, interleukin (IL)-1beta, and cyclooxygenase-2, as well as the process of osteoclast differentiation. Therefore, we evaluated whether a p38alpha MAPK inhibitor, indole-5-carboxamide (SD-282), could modulate cartilage and bone destruction in a mouse model of RA induced with bovine type II collagen [collagen-induced arthritis (CIA)]. In mice with early disease, SD-282 treatment significantly improved clinical severity scores, reduced bone and cartilage loss, and reduced mRNA levels of proinflammatory genes in paw tissue, including IL-1beta, IL-6, and cyclooxygenase-2. Notably, SD-282 treatment of mice with advanced disease resulted in significant improvement in clinical severity scoring and paw swelling, a reversal in bone and cartilage destruction as assessed by histology, bone volume fraction and thickness, and three-dimensional image analysis. These changes were accompanied by reduced osteoclast number and lowered levels of serum cartilage oligomeric matrix protein, a marker of cartilage breakdown. Thus, in a model of experimental arthritis associated with significant osteolysis, p38alpha MAPK inhibition not only attenuates disease progression but also reverses cartilage and bone destruction in mice with advanced CIA disease.
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