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Chen A, Cai Q. Association of Biomarkers Such as CA, TP, TES and ALP With Osteoarthritis Risk: A Mendelian Randomized Study. Int J Rheum Dis 2025; 28:e70033. [PMID: 39854182 DOI: 10.1111/1756-185x.70033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/24/2024] [Accepted: 12/19/2024] [Indexed: 01/26/2025]
Abstract
OBJECTIVE Osteoarthritis is a common joint disease caused by a variety of risk factors, and it has been found that many biochemical markers are abnormal in peripheral blood and urine of patients with OA. The aim of this study was to elucidate the causal relationship between biomarkers associated with these processes and OA using Mendelian randomization (MR) analysis. METHOD The inverse variance weighted (IVW) approach to MR was primarily used to explore causal associations between exposures and outcomes using publicly available genetic variants from large genome-wide association studies (GWAS). That is, single nucleotide polymorphisms (SNPs) associated with 35 human blood and urine markers (363 228 healthy participants) were used as exposure, and osteoarthritis, hip osteoarthritis, and knee osteoarthritis were used as outcome variables, with the aim of exploring the causal relationship between 35 human blood and urine markers and osteoarthritis. MR-Egger, weighted median (WM), and simple and weighted models were used as complementary methods to IVW to assess the reliability of causality. Steiger's test was used to confirm whether the causal relationship between exposure and outcome was biased by reverse causality. Sensitivity analyses used Cochran's Q statistic and funnel plots to detect heterogeneity, and the MR-Egger intercept test and leave-one-out to assess horizontal multidimensionality. RESULTS Our MR analysis study identified the protective effects of CA, TP, ALB, SHBG, and VITD on OA and the pathogenic effects of TES, ALP, GGT, CRP, and CHOL on OA. It suggests that the above 10 hematological and urinary markers have the potential to be important indicators for the clinical diagnosis of OA as well as for the assessment of therapeutic efficacy and disease progression. CONCLUSION This MR analysis reinforces the importance of biomarkers in the diagnosis and prediction of OA. Future studies should further investigate the mechanisms of these biomarkers and their potential as therapeutic targets for OA.
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Affiliation(s)
- Anqi Chen
- College of Medicine, Wuhan University of Science and Technology, Hubei, China
| | - Qiang Cai
- Department of Orthopedics, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Hubei, China
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Wang H, Zhao X, Wu Z. Mechanism of drug-pairs Astragalus Mongholicus-Largehead Atractylodes on treating knee osteoarthritis investigated by GEO gene chip with network pharmacology and molecular docking. Medicine (Baltimore) 2024; 103:e38699. [PMID: 38968529 PMCID: PMC11224889 DOI: 10.1097/md.0000000000038699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 06/04/2024] [Indexed: 07/07/2024] Open
Abstract
Investigations into the therapeutic potential of Astragalus Mongholicus (AM, huáng qí) and Largehead Atractylodes (LA, bái zhú) reveal significant efficacy in mitigating the onset and progression of knee osteoarthritis (KOA), albeit with an elusive mechanistic understanding. This study delineates the primary bioactive constituents and their molecular targets within the AM-LA synergy by harnessing the comprehensive Traditional Chinese Medicine (TCM) network databases, including TCMSP, TCMID, and ETCM. Furthermore, an analysis of 3 gene expression datasets, sourced from the gene expression omnibus database, facilitated the identification of differential genes associated with KOA. Integrating these findings with data from 5 predominant databases yielded a refined list of KOA-associated targets, which were subsequently aligned with the gene signatures corresponding to AM and LA treatment. Through this alignment, specific molecular targets pertinent to the AM-LA therapeutic axis were elucidated. The construction of a protein-protein interaction network, leveraging the shared genetic markers between KOA pathology and AM-LA intervention, enabled the identification of pivotal molecular targets via the topological analysis facilitated by CytoNCA plugins. Subsequent GO and KEGG enrichment analyses fostered the development of a holistic herbal-ingredient-target network and a core target-signal pathway network. Molecular docking techniques were employed to validate the interaction between 5 central molecular targets and their corresponding active compounds within the AM-LA complex. Our findings suggest that the AM-LA combination modulates key biological processes, including cellular activity, reactive oxygen species modification, metabolic regulation, and the activation of systemic immunity. By either augmenting or attenuating crucial signaling pathways, such as MAPK, calcium, and PI3K/AKT pathways, the AM-LA dyad orchestrates a comprehensive regulatory effect on immune-inflammatory responses, cellular proliferation, differentiation, apoptosis, and antioxidant defenses, offering a novel therapeutic avenue for KOA management. This study, underpinned by gene expression omnibus gene chip analyses and network pharmacology, advances our understanding of the molecular underpinnings governing the inhibitory effects of AM and LA on KOA progression, laying the groundwork for future explorations into the active components and mechanistic pathways of TCM in KOA treatment.
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Affiliation(s)
- Hui Wang
- Jinan Third People’s Hospital, Affiliated Jinan Third People’s Hospital of Jining Medical University, Jining, Shandong, China
| | - Xinyou Zhao
- Yanzhou People’s Hospital, Jining Medical University, Jining, Shandong, China
| | - Zixuan Wu
- Hunan University of Traditional Chinese Medicine, Changsha, Hunan Province, China
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Singh S, Jindal D, Khanna R. sCTX II is a better biomarker than sMMP-3 to identify early knee osteoarthritis. J Orthop Res 2023; 41:2455-2461. [PMID: 37132376 DOI: 10.1002/jor.25582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/01/2023] [Indexed: 05/04/2023]
Abstract
The aim of this study is to assess the ability of serum MMP-3 and serum CTX-II levels to differentiate between normal and early knee osteoarthritis case (eKOA). Subjects with clinical features of primary knee osteoarthritis of K-L Grade I and K-L Grade II with ages more than 45 years were included in the case group (98), and healthy adults with ages less than 40 years were included in the control group (80). Those having knee pain for the last 3 months but having no radiological features were labeled as K-L grade I and those having minimal osteophytes on radiographs were labeled as K-L Grade II. Antero-posterior views of knee and serum levels of MMP-3 and CTX II were estimated. Cases show significantly higher values of both biomarkers than in controls (p < 0.0001). Both biomarkers show significantly higher values with an increase in K-L Grades, that is, K-L Grade 0 versus I (MMP-3: p = 0.003; CTX-II: p = 0.002), K-L Grade I versus II (MMP-3: p < 0.000; CTX-II: p < 0.000). Multivariate analysis shows the dependence of both biomarkers only on K-L Grades. ROC analysis suggests cutoff value between KL Grade 0 and Grade I (MMP-3: 12.25 ng/mL; CTX II: 407.50 pg/mL) and between K L Grade I and Grade II (MMP-3: 18.37 ng/mL; CTX II: 528.00 pg/mL). The discriminating ability of CTX II is superior between normal population and eKOA (CTX II: Accuracy: 66.83%, p = 0.0002; MMP-3: Accuracy: 50.39%, p = 0.138), but MMP-3 is superior than CTX II between eKOA and mild KOA (CTX II:67.52%, p < 0.000; MMP-3: 70.69%, p < 0.000).
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Affiliation(s)
- Sudhir Singh
- Department of Orthopaedics, Teerthankar Mahaveer Medical College & Research Centre, Moradabad, Uttar Pradesh, India
| | - Divyam Jindal
- Department of Orthopaedics, Teerthankar Mahaveer Medical College & Research Centre, Moradabad, Uttar Pradesh, India
| | - Rajat Khanna
- Department of Orthopaedics, Teerthankar Mahaveer Medical College & Research Centre, Moradabad, Uttar Pradesh, India
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Tong SX, Li RS, Wang D, Xie XM, Ruan Y, Huang L. Artificial intelligence technology and ultrasound-guided nerve block for analgesia in total knee arthroplasty. World J Clin Cases 2023; 11:7026-7033. [PMID: 37946775 PMCID: PMC10631398 DOI: 10.12998/wjcc.v11.i29.7026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/14/2023] [Accepted: 09/22/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Knee diseases are more common in middle-aged and elderly people, so artificial knee replacement is also more used in middle-aged and elderly people. Although the patient's pain can be reduced through surgery, often accompanied by moderate pain after surgery and neutralization, which not only increases the psychological burden of the patient, but also greatly reduces the postoperative recovery effect, and may also lead to the occurrence of postoperative adverse events in severe cases. AIM To investigate the analgesic effect of artificial intelligence (AI) and ultrasound-guided nerve block in total knee arthroplasty (TKA). METHODS A total of 92 patients with TKA admitted to our hospital from January 2021 to January 2022 were opted and divided into two groups according to the treatment regimen. The control group received combined spinal-epidural anesthesia. The research group received AI technique combined with ultrasound-guided nerve block anesthesia. The sensory block time, motor block time, visual analogue scale (VAS) at different time points and complications were contrasted between the two groups. RESULTS The time of sensory block onset and sensory block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of sensory block in the research group was significantly longer than those in the control group (P < 0.05). The time of motor block onset and motor block perfection in the research group was shorter than those in the control group, but the results had no significant difference (P > 0.05). Duration of motor block in the research group was significantly longer than those in the control group. The VAS scales of the research group were significantly lower than that of the control group at different time points (P < 0.05). The postoperative hip flexion and abduction range of motion in the research group were significantly better than those in the control group at different time points (P < 0.05). The incidence of complications was significantly lower in the research group than in the control group (P = 0.049). CONCLUSION In TKA, the combination of AI technology and ultrasound-guided nerve block has a significantly effect, with fewer postoperative complications and significantly analgesic effect, which is worthy of application.
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Affiliation(s)
- Sheng-Xiong Tong
- Department of Pain Management, Wuhan First Hospital, Wuhan 430033, Hubei Province, China
| | - Ren-Song Li
- Department of Orthopaedics, Wuhan Wuchang Hospital, Wuhan 430063, Hubei Province, China
| | - Dan Wang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiao-Meng Xie
- Department of Nursing, Huanggang Central Hospital, Huanggang 438000, Hubei Province, China
| | - Yuan Ruan
- Department of Orthopaedics, Huanggang Central Hospital, Huanggang 438000, Hubei Province, China
| | - Lin Huang
- Department of Orthopaedics, Huanggang Central Hospital, Huanggang 438000, Hubei Province, China
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Sandhu A, Rockel JS, Lively S, Kapoor M. Emerging molecular biomarkers in osteoarthritis pathology. Ther Adv Musculoskelet Dis 2023; 15:1759720X231177116. [PMID: 37359177 PMCID: PMC10288416 DOI: 10.1177/1759720x231177116] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 04/24/2023] [Indexed: 06/28/2023] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis resulting in joint discomfort and disability, culminating in decline in life quality. Attention has been drawn in recent years to disease-associated molecular biomarkers found in readily accessible biofluids due to low invasiveness of acquisition and their potential to detect early pathological molecular changes not observed with traditional imaging methodology. These biochemical markers of OA have been found in synovial fluid, blood, and urine. They include emerging molecular classes, such as metabolites and noncoding RNAs, as well as classical biomarkers, like inflammatory mediators and by-products of degradative processes involving articular cartilage. Although blood-based biomarkers tend to be most studied, the use of synovial fluid, a more isolated biofluid in the synovial joint, and urine as an excreted fluid containing OA biomarkers can offer valuable information on local and overall disease activity, respectively. Furthermore, larger clinical studies are required to determine relationships between biomarkers in different biofluids, and their impacts on patient measures of OA. This narrative review provides a concise overview of recent studies of OA using these four classes of biomarkers as potential biomarker for measuring disease incidence, staging, prognosis, and therapeutic intervention efficacy.
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Affiliation(s)
- Amit Sandhu
- Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Jason S. Rockel
- Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Starlee Lively
- Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Mohit Kapoor
- Division of Orthopaedics, Osteoarthritis Research Program, Schroeder Arthritis Institute, University Health Network, 60 Leonard Avenue, 5th Floor Krembil Discovery Tower, Toronto, ON M5G 2C4, Canada
- Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
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Campos LD, de Almeida Santos Junior V, Pimentel JD, Fernandes Carregã GL, Betim Cazarin CB. Collagen supplementation in skin and orthopedic diseases: A review of the literature. Heliyon 2023; 9:e14961. [PMID: 37064452 PMCID: PMC10102402 DOI: 10.1016/j.heliyon.2023.e14961] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 03/17/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023] Open
Abstract
Collagen is one of the main components of the extracellular matrix of the dermis and articular cartilage and influences the body's mechanical, organizational, and tissue formation properties. Produced from food industry by-products, it is considered a nutraceutical product widely used as an ingredient or supplement in food, pharmaceutical, and cosmetic industries. This study aimed to conduct a literature review on the scientific evidence regarding the beneficial effects of collagen consumption in the treatment of skin and orthopedic diseases. Literature data have shown that hydrolyzed collagen supplementation promotes skin changes, such as decreased wrinkle formation; increased skin elasticity; increased hydration; increased collagen content, density, and synthesis, which are factors closely associated with aging-related skin damage. Regarding orthopedic changes, collagen supplementation increases bone strength, density, and mass; improves joint stiffness/mobility, and functionality; and reduces pain. These aspects are associated with bone loss due to aging and damage caused by strenuous physical activity. Thus, this review addresses the economic and health potential of this source of amino acids and bioactive peptides extracted from food industry by-products.
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Soluble and EV-Associated Diagnostic and Prognostic Biomarkers in Knee Osteoarthritis Pathology and Detection. Life (Basel) 2023; 13:life13020342. [PMID: 36836699 PMCID: PMC9961153 DOI: 10.3390/life13020342] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/13/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
Osteoarthritis (OA) is the most common degenerative disease of the connective tissue of the human musculoskeletal system. Despite its widespread prevalence, there are many limitations in its diagnosis and treatment. OA diagnosis currently relies on the presence of clinical symptoms, sometimes accompanied by changes in joint X-rays or MRIs. Biomarkers help not only to diagnose early disease progression but also to understand the process of OA in many ways. In this article, we briefly summarize information on articular joints and joint tissues, the pathogenesis of OA and review the literature about biomarkers in the field of OA, specifically inflammatory cytokines/chemokines, proteins, miRNA, and metabolic biomarkers found in the blood, synovial fluid and in extracellular vesicles.
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Convill JG, Tawy GF, Freemont AJ, Biant LC. Clinically Relevant Molecular Biomarkers for Use in Human Knee Osteoarthritis: A Systematic Review. Cartilage 2021; 13:1511S-1531S. [PMID: 32680434 PMCID: PMC8808945 DOI: 10.1177/1947603520941239] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
OBJECTIVE Biomarkers in osteoarthritis (OA) could serve as objective clinical indicators for various disease parameters, and act as surrogate endpoints in clinical trials for disease-modifying drugs. The aim of this systematic review was to produce a comprehensive list of candidate molecular biomarkers for knee OA after the 2013 ESCEO review and discern whether any have been studied in sufficient detail for use in clinical settings. DESIGN MEDLINE and Embase databases were searched between August 2013 and May 2018 using the keywords "knee osteoarthritis," "osteoarthritis," and "biomarker." Studies were screened by title, abstract, and full text. Human studies on knee OA that were published in the English language were included. Excluded were studies on genetic/imaging/cellular markers, studies on participants with secondary OA, and publications that were review/abstract-only. Study quality and bias were assessed. Statistically significant data regarding the relationship between a biomarker and a disease parameter were extracted. RESULTS A total of 80 studies were included in the final review and 89 statistically significant individual molecular biomarkers were identified. C-telopeptide of type II collagen (CTXII) was shown to predict progression of knee OA in urine and serum in multiple studies. Synovial fluid vascular endothelial growth factor concentration was reported by 2 studies to be predictive of knee OA progression. CONCLUSION Despite the clear need for biomarkers of OA, the lack of coordination in current research has led to incompatible results. As such, there is yet to be a suitable biomarker to be used in a clinical setting.
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Affiliation(s)
- James G Convill
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Gwenllian F Tawy
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Anthony J Freemont
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Leela C Biant
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
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Lv Z, Yang YX, Li J, Fei Y, Guo H, Sun Z, Lu J, Xu X, Jiang Q, Ikegawa S, Shi D. Molecular Classification of Knee Osteoarthritis. Front Cell Dev Biol 2021; 9:725568. [PMID: 34513847 PMCID: PMC8429960 DOI: 10.3389/fcell.2021.725568] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/09/2021] [Indexed: 01/15/2023] Open
Abstract
Knee osteoarthritis (KOA) is the most common form of joint degeneration with increasing prevalence and incidence in recent decades. KOA is a molecular disorder characterized by the interplay of numerous molecules, a considerable number of which can be detected in body fluids, including synovial fluid, urine, and blood. However, the current diagnosis and treatment of KOA mainly rely on clinical and imaging manifestations, neglecting its molecular pathophysiology. The mismatch between participants' molecular characteristics and drug therapeutic mechanisms might explain the failure of some disease-modifying drugs in clinical trials. Hence, according to the temporal alteration of representative molecules, we propose a novel molecular classification of KOA divided into pre-KOA, early KOA, progressive KOA, and end-stage KOA. Then, progressive KOA is furtherly divided into four subtypes as cartilage degradation-driven, bone remodeling-driven, inflammation-driven, and pain-driven subtype, based on the major pathophysiology in patient clusters. Multiple clinical findings of representatively investigated molecules in recent years will be reviewed and categorized. This molecular classification allows for the prediction of high-risk KOA individuals, the diagnosis of early KOA patients, the assessment of therapeutic efficacy, and in particular, the selection of homogenous patients who may benefit most from the appropriate therapeutic agents.
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Affiliation(s)
- Zhongyang Lv
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yannick Xiaofan Yang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jiawei Li
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuxiang Fei
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Hu Guo
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Ziying Sun
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jun Lu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xingquan Xu
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Qing Jiang
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Shiro Ikegawa
- Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Science (IMS, RIKEN), Tokyo, Japan
| | - Dongquan Shi
- State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
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Rim YA, Nam Y, Park N, Lee K, Jung H, Jung SM, Lee J, Ju JH. Characterization of Early-Onset Finger Osteoarthritis-Like Condition Using Patient-Derived Induced Pluripotent Stem Cells. Cells 2021; 10:cells10020317. [PMID: 33557199 PMCID: PMC7913990 DOI: 10.3390/cells10020317] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/10/2021] [Accepted: 01/27/2021] [Indexed: 12/23/2022] Open
Abstract
Early osteoarthritis (OA)-like symptoms are difficult to study owing to the lack of disease samples and animal models. In this study, we generated induced pluripotent stem cell (iPSC) lines from a patient with a radiographic early-onset finger osteoarthritis (efOA)-like condition in the distal interphalangeal joint and her healthy sibling. We differentiated those cells with similar genetic backgrounds into chondrogenic pellets (CPs) to confirm efOA. CPs generated from efOA-hiPSCs (efOA-CPs) showed lower levels of COL2A1, which is a key marker of hyaline cartilage after complete differentiation, for 21 days. Increase in pellet size and vacuole-like morphologies within the pellets were observed in the efOA-CPs. To analyze the changes occurred during the development of vacuole-like morphology and the increase in pellet size in efOA-CPs, we analyzed the expression of OA-related markers on day 7 of differentiation and showed an increase in the levels of COL1A1, RUNX2, VEGFA, and AQP1 in efOA-CPs. IL-6, MMP1, and MMP10 levels were also increased in the efOA-CPs. Taken together, we present proof-of-concept regarding disease modeling of a unique patient who showed OA-like symptoms.
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Affiliation(s)
- Yeri Alice Rim
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
| | - Yoojun Nam
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
| | - Narae Park
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
| | - Kijun Lee
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
| | - Hyerin Jung
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
| | - Seung Min Jung
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
| | - Jennifer Lee
- Department of Internal Medicine, Division of Rheumatology, Institute of Medical Science, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea;
| | - Ji Hyeon Ju
- Catholic iPSC Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (Y.A.R.); (Y.N.); (N.P.); (K.L.); (H.J.); (S.M.J.)
- Department of Internal Medicine, Division of Rheumatology, Institute of Medical Science, College of Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul 06591, Korea;
- Correspondence: ; Tel.: +82-2-2258-6895
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Cheng H, Hao B, Sun J, Yin M. C-Terminal Cross-Linked Telopeptides of Type II Collagen as Biomarker for Radiological Knee Osteoarthritis: A Meta-Analysis. Cartilage 2020; 11:512-520. [PMID: 30221987 PMCID: PMC7488952 DOI: 10.1177/1947603518798884] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND C-terminal cross-linked telopeptides of type II collagen (CTX-II) are one of the most frequently assessed markers for osteoarthritis (OA) diagnosis. The aim of this meta-analysis was to confirm the diagnostic value of urinary CTX-II in knee OA. MATERIALS AND METHODS PubMed, ScienceDirect, and EMBASE were searched for studies measured urinary CTX-II in patients with knee OA and in healthy controls. Urinary CTX-II levels were compared between knee OA patients and controls. Differences between groups were expressed as standardized mean differences (SMD) when individual outcomes were measured with different scales. Otherwise, outcomes were presented as mean differences (MD). Subgroup analyses were also conducted to compare efficiency of urinary CTX-II between Kellgren-Lawrence (KL) classification, genders, ethnicities, and study size. RESULTS Thirteen studies involved a total of 2856 participants were included. Pooled SMD showed that urinary CTX-II levels were significantly elevated in knee OA group compared to controls (SMD 0.82; 95% CI 0.41-1.24; P < 0.0001). For KL 3 to 4 versus KL 2, higher urinary CTX-II levels were found in severe knee OA patients. Subgroup analyses revealed that urinary CTX-II performed better in females as compared with males and in European subjects as compared with Asian population. Also, study size did not influence the statistic results. CONCLUSION This is the largest scale meta-analysis assessing the diagnostic performance of urinary CTX-II levels as biomarker for knee OA. According to our findings, urinary CTX-II levels have a potential to distinguish knee OA patients from healthy controls which can serve as biomarker for knee OA.
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Affiliation(s)
- HongBin Cheng
- Department of Orthopedics, The Fourth Central Hospital, Tianjin City, China
| | - Baoxi Hao
- Department of Orthopedics, The Fourth Central Hospital, Tianjin City, China
| | - Jingtao Sun
- Department of Orthopedics, The Fourth Central Hospital, Tianjin City, China
| | - Mingxi Yin
- Department of Orthopedics, The Fourth Central Hospital, Tianjin City, China
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Gladkova EV. The role of matrix metalloproteinases in early and late gonarthrosis manifestations. RUSSIAN OPEN MEDICAL JOURNAL 2020. [DOI: 10.15275/rusomj.2020.0302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The aim of this research was to study the specifics of the matrix metallopeptidase system in early and late gonarthrosis (GA) manifestations. Material and Methods — 37 patients of the main group (0-I stages of GA), 30 patients of the comparison group (III-IV stages of GA) and 30 healthy individuals of the control group underwent sonography and T2-relaxometry of their knee joints. The 24-h excretion of urinary C-telopeptide fragments of type II collagen (СTX-II) as well as serum concentrations of matrix metalloproteinases-3 and -8 (MMP-3, MMP-8), and tissue inhibitor of metalloproteinases (TIMP-1) were also registered. Results — We detected increases in urinary СTX-II to 3.9 [2.5; 4.5] mg/d, MMP-8 to 364.7 [215; 434] pg/ml and TIMP-1 to 806 [559; 1157] pg/ml in the main group; to 9.7 [6.8; 10.2] mg/d, 579 [463; 663] pg/ml and 1256 [1029; 1330] pg/ml in the comparison group. The presence (p=0.04) of strong positive correlation (R=0.7) between the 24-h urinary СTX-II excretion and the change of MRI-signal characteristics for the areas of hyaline cartilage under the heaviest load on knee joints T2 relaxometry evidence was observed as well as the presence (p=0.001) of strong positive correlation (R=0.7) between MMP-8 and 24-h urinary СTX-II extraction. In early GA stages a strong positive correlation (R=0.6) was observed between MMP-8 and TIMP-1 (p=0.04) as well as 24-h urinary СTX-II excretion and TIMP-1 (R=0.5) at p˂0.001). Conclusion — Type II collagen degradation with MMP-8/TIMP-1 imbalance is one of the relevant mechanisms of the hyaline articular cartilage extracellular matrix disorganization in early and late GA evidences. The rearrangement of correlations between MMP-8 and TIMP-1 indicates the change in interaction mechanisms for GA proteolytic enzyme system components.
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Arunrukthavon P, Heebthamai D, Benchasiriluck P, Chaluay S, Chotanaphuti T, Khuangsirikul S. Can urinary CTX-II be a biomarker for knee osteoarthritis? ARTHROPLASTY 2020; 2:6. [PMID: 35236476 PMCID: PMC8796402 DOI: 10.1186/s42836-020-0024-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 01/13/2020] [Indexed: 12/04/2022] Open
Abstract
Background Early diagnosis of knee osteoarthritis (OA) remains a diagnostic challenge. Urinary C-terminal cross-linked telopeptide of type II collagen (urinary CTX-II) is one of the potential OA biomarkers. However, conclusive evidence regarding the use of this biomarker as a tool for early diagnosis is still lacking. The purposes of this study were to compare urinary CTX-II levels in patients with knee OA and in healthy controls, to evaluate the correlation between urinary CTX-II levels, radiographic severity of OA, and patient-reported outcomes and to evaluate the effect of age and gender on urinary CTX-II levels in the Asian populations. Methods Two groups were studied. The OA group included 78 patients with knee OA aged > 40 years who met the diagnostic criteria for knee OA described by the American College of Rheumatology (ACR). The control group consisted of 51 healthy participants age > 40 years without clinical or radiographic evidence of knee OA. Bilateral knee radiographs were taken and classified according to the Kellgren and Lawrence (KL) grading system. Urinary CTX-II was measured using a competitive ELISA test and Western Ontario and Mcmaster Universities Arthritis Index (WOMAC) was also recorded in all participants. Results Urinary CTX-II was significantly higher in the OA group than in the control group (p < 0.001). The severe knee OA group (KL grade 3 and 4) had higher urinary CTX-II levels than mild knee OA group (KL grade 2) but the difference did not reach statistical significance (p = 0.2). There was a moderate correlation between urinary CTX-II levels and KL grades (r = 0.405, p < 0.001) and a weak correlation between urinary CTX-II levels and WOMAC index scores (r = 0.367, p < 0.001). Multiple regression analysis showed that urinary CTX-II was independently associated with KL grades. Whereas age, gender, and WOMAC index had no statistically significant influence on the urinary CTX-II levels. Conclusions Patients with knee OA had higher urinary CTX-II levels than healthy controls. Moreover, levels of urinary CTX-II were independently correlated with radiographic severity of knee OA. Age, gender, and patient-reported outcomes exerted no effect on the urinary CTX-II levels. Level of evidence Diagnostic Level III.
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14
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García-Alvarado FJ, Delgado-Aguirre HA, Rosales-González M, González-Martínez MDR, Ruiz-Flores P, González-Galarza FF, Arellano Perez Vertti RD. Analysis of Polymorphisms in the MATN3 and DOT1L Genes and CTX-II Urinary Levels in Patients with Knee Osteoarthritis in a Northeast Mexican-Mestizo Population. Genet Test Mol Biomarkers 2020; 24:105-111. [DOI: 10.1089/gtmb.2019.0179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Francisco J. García-Alvarado
- Departamento de Investigación, Universidad Juárez del Estado de Durango, Facultad de Ciencias de la Salud, Gómez Palacio Durango, México
| | - Héctor A. Delgado-Aguirre
- Departamento de Trasplantes, Instituto Mexicano del Seguro Social Hospital de Especialidades 71, Torreón, México
| | - Manuel Rosales-González
- Departamento de Investigación, Universidad Juárez del Estado de Durango, Facultad de Ciencias de la Salud, Gómez Palacio Durango, México
| | | | - Pablo Ruiz-Flores
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad Autónoma de Coahuila, Torreón, México
| | - Faviel F. González-Galarza
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad Autónoma de Coahuila, Torreón, México
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Munjal A, Bapat S, Hubbard D, Hunter M, Kolhe R, Fulzele S. Advances in Molecular biomarker for early diagnosis of Osteoarthritis. Biomol Concepts 2019; 10:111-119. [PMID: 31401621 DOI: 10.1515/bmc-2019-0014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 05/12/2019] [Indexed: 12/16/2022] Open
Abstract
Osteoarthritis (OA) is a chronic degenerative joint disease. The pathogenesis is poorly understood. What is known is that OA is characterized by imbalance in anabolic and catabolic gene expression in articular chondrocytes. This results in bone on bone articulations resulting in impaired mobility and joint pain. Although the cause of OA is unknown, comorbidities include: aging, obesity, and mechanical stress. Currently the only diagnostic modalities are radiology and physical examination, and early detection is rare. Biomarkers are quantifiable substances, and their presence can be suggestive of a certain phenomenon or disease. Biomarkers are popular for early diagnosis for pathological conditions in the fields of oncology, cardiology, and endocrinology. This review has systematically reviewed the literature about biomarkers in the field of OA, specifically protein, miRNA, and metabolic biomarkers found in the blood, urine, and synovial fluid.
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Affiliation(s)
- Akul Munjal
- Department of Orthopedics, Augusta University, Augusta, GA
| | - Santul Bapat
- Department of Orthopedics, Augusta University, Augusta, GA
| | - Daniel Hubbard
- Department of Orthopedics, Augusta University, Augusta, GA
| | - Monte Hunter
- Department of Orthopedics, Augusta University, Augusta, GA
| | - Ravindra Kolhe
- Department of Pathology, Augusta University, Augusta, GA
| | - Sadanand Fulzele
- Department of Orthopedics, Augusta University, Augusta, GA.,Institute of Regenerative and Reparative medicine, Augusta University, Augusta, GA
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16
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Cartilage oligomeric matrix protein, C-terminal cross-linking telopeptide of type II collagen, and matrix metalloproteinase-3 as biomarkers for knee and hip osteoarthritis (OA) diagnosis: a systematic review and meta-analysis. Osteoarthritis Cartilage 2019; 27:726-736. [PMID: 30391538 DOI: 10.1016/j.joca.2018.10.009] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/25/2018] [Accepted: 10/08/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE This study was design to examine the diagnostic performance of cartilage oligomeric matrix protein (COMP), C-terminal cross-linking telopeptide of type II collagen (CTX-II), and matrix metalloproteinase-3 (MMP-3) as biomarker for knee and hip OA. METHODS Systematic search on multiple databases was completed in January 2018 using certain keywords. COMP, CTX-II, MMP-3 levels in knee and hip OA patients and healthy individuals were collected and calculated. Differences between subgroups were expressed as standardized mean differences (SMD). Subgroup analyses were performed to compare COMP, CTX-II, and MMP-3 performance between measuring sources, genders, large and small sample size and diagnostic criteria for OA patients. RESULTS A moderate performance of COMP in distinguishing between knee (SMD: 0.68; 95% confidence intervals (CI): 0.43-0.93; P < 0.0001) or hip (SMD: 0.25; 95% CI, 0.10, 0.40; P = 0.0008) OA patients and controls were found. CTX-II showed a moderated standardised mean differences (SMD) of 0.48 (95% CI, 0.32, 0.64; P < 0.0001) in the detection of knee OA and a large SMD of 0.76 (95% CI, 0.09, 1.42; P = 0.03) in diagnosing hip OA. A small SMD of 0.32 (95% CI, -0.03, 0.67; P = 0.07) was found for MMP-3 performance and the results did not reach statistic significance. Progression study revealed potential effectiveness of serum COMP in predicting OA progression. Subgroup analysis showed that serum COMP and urinary CTX-II performed better in male than female. Study size and diagnostic criteria did not significantly influence the pooled SMD, but they might be the sources of heterogeneity among studies. CONCLUSION The overall results indicates that serum COMP and urinary CTX-II can distinguish between knee or hip OA patients and control subjects. Serum COMP is effective in predicting OA progression.Further researches with rigorous study design and a larger sample size are required to validate our findings.
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Saberi Hosnijeh F, Bierma-Zeinstra SM, Bay-Jensen AC. Osteoarthritis year in review 2018: biomarkers (biochemical markers). Osteoarthritis Cartilage 2019; 27:412-423. [PMID: 30552966 DOI: 10.1016/j.joca.2018.12.002] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 11/23/2018] [Accepted: 12/05/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The aim of this narrative review is to summarize important findings from biochemical marker studies relevant to osteoarthritis (OA) in the context of new discoveries and clinical and scientific need. DESIGN We conducted a systematic search of electronic medical databases (Embase, Medline, Web of Science, Cochrane central) between 01-03-2017 and 31-03-2018. The search was restricted to human studies, English language and full text available publications while reviews were excluded. Only papers describing protein based biomarkers measured in human body fluids (blood, urine and synovial fluid (SF)) were included. Of the 992 papers, 86 were reviewed here, with inclusion primarily based on relevance to OA biochemical markers. RESULTS This review highlights a selection of studies based on their quality and perceived importance to the field mainly including those that1 evaluate prognostic value of biomarkers for OA progression (i.e., biomarkers reflecting change in composition of joint tissues and biomarkers of inflammation)2, help in assessment of intervention efficacy, and3 are innovative and uncover new candidate biomarkers, or use new approaches in biomarker discovery. CONCLUSIONS Key findings and implications for possible clinical utility of biochemical markers are summarized and discussed. Given the paucity of robust biomarkers within the field, and the heterogeneity of the condition, enormous works are needed for development and validation of novel and clinically applicable biomarkers to reduce the impact of this highly prevalent and debilitating condition.
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Affiliation(s)
- F Saberi Hosnijeh
- Immunology Department, Erasmus University Medical Center, Rotterdam, the Netherlands; Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, the Netherlands.
| | - S M Bierma-Zeinstra
- Department of General Practice, Erasmus University Medical Center, Rotterdam, the Netherlands.
| | - A C Bay-Jensen
- Biomarker and Research, Nordic Bioscience, Herlev, Denmark.
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Hafsi K, McKay J, Li J, Lana JF, Macedo A, Santos GS, Murrell WD. Nutritional, metabolic and genetic considerations to optimise regenerative medicine outcome for knee osteoarthritis. J Clin Orthop Trauma 2019; 10:2-8. [PMID: 30705524 PMCID: PMC6349648 DOI: 10.1016/j.jcot.2018.10.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/08/2018] [Indexed: 12/20/2022] Open
Abstract
Knee osteoarthritis (KOA) is a multifactorial degenerative disorder of joints, affecting the world's population over the age of 65 and with a higher prevalence in females. KOA is responsible for many age associated joint problems such as stiffness and pain. Conventional methods for managing KOA such as nonsteroidal anti-inflammatory drugs (NSAID) may not improve pain or alter the disease progression and may have adverse side effects. Non-pharmacological management of OA is fundamental to management of functional limitations and provides effective symptom relief but has not shown that disease progression can be altered. Regenerative medicine is a relatively new approach which aims to induce cellular regeneration and promote self-healing through minimally invasive methods. The use of regenerative medicine slowed the progression of KOA and revealed significant improvements, yet further investigations are required to optimize the outcomes. Nutritional and metabolic aspects such as supplementations, vitamins and minerals were proven to have an impact on the progression of KOA. Genetic variations are rapidly inspected to identify any potential influence of these variations in the predisposition and diagnosis of KOA. Further supporting evidence suggests the potential influence of metabolic, nutritional and genetic aspects in optimizing the outcomes of regenerative medicine in the management of KOA.
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Affiliation(s)
- Kholoud Hafsi
- Emirates Integra Medical and Surgery Centre, Dubai, United Arab Emirates
| | - Janine McKay
- Emirates Integra Medical and Surgery Centre, Dubai, United Arab Emirates
| | - Jinjie Li
- Emirates Integra Medical and Surgery Centre, Dubai, United Arab Emirates
| | - José Fábio Lana
- Instituto do Osso e da Cartilagem, Indaiatuba, State of São Paulo, Brazil
| | - Alex Macedo
- Instituto do Osso e da Cartilagem, Indaiatuba, State of São Paulo, Brazil
| | | | - William D. Murrell
- Emirates Integra Medical and Surgery Centre, Dubai, United Arab Emirates
- Emirates Healthcare, Dubai, United Arab Emirates
- Landstuhl Regional Medical Center, Landstuhl, Germany
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Ren G, Krawetz RJ. Biochemical Markers for the Early Identification of Osteoarthritis: Systematic Review and Meta-Analysis. Mol Diagn Ther 2018; 22:671-682. [PMID: 30377978 DOI: 10.1007/s40291-018-0362-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND There is a desperate need for the reliable detection of osteoarthritis (OA) at the early stage when patients are likely to benefit most from disease interventions. A variety of biochemical markers have been proposed, but their reliability varies among studies. OBJECTIVE In this review, we aimed to answer the following questions: (1) are there biochemical markers that are differentially expressed in early OA versus healthy subjects, and (2) if so, what is the diagnostic value of these biomarkers for early OA? METHODS Embase, PubMed, and Web of Science were searched to obtain all relevant studies up to March 2018, and studies comparing the biochemical markers between early OA and healthy controls were selected. The Downs and Black checklist was used to assess the risk of bias. Biomarkers that were investigated in five or more different populations were pooled for meta-analysis. A meta-regression analysis was performed to explore possible explanations for the heterogeneity of studies. RESULT In total, 26 articles met the criteria for the qualitative synthesis and 17 articles for the final quantitative synthesis. N-terminal crosslinked telopeptide of type I collagen (NTX-I) was the only biomarker found to be differently expressed in patients with early OA versus controls, without significant heterogeneity among studies (I2 = 0%, [Formula: see text] = 1.695, p = 0.792). The meta-regression analysis identified that sample size and affected joint possibly explained the heterogeneity among studies. CONCLUSION Although a wide range of biomarkers has been previously investigated in early OA, the diagnostic value of these biomarkers could not be determined because due to a low number of studies regarding any given biomarker. Large prospective and adequately powered studies are therefore required to validate these (and other) biomarkers for identifying early OA.
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Affiliation(s)
- Guomin Ren
- Cumming School of Medicine, McCaig Institute, University of Calgary, HRIC 3AA14, 3330 Hospital Dr. NW, Calgary, AB, T2N 4N1, Canada
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada
| | - Roman J Krawetz
- Cumming School of Medicine, McCaig Institute, University of Calgary, HRIC 3AA14, 3330 Hospital Dr. NW, Calgary, AB, T2N 4N1, Canada.
- Biomedical Engineering Graduate Program, University of Calgary, Calgary, AB, Canada.
- Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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Tan Y, Yao X, Dai Z, Wang Y, Lv G. Bone morphogenetic protein 2 alleviated intervertebral disc degeneration through mediating the degradation of ECM and apoptosis of nucleus pulposus cells via the PI3K/Akt pathway. Int J Mol Med 2018; 43:583-592. [PMID: 30387830 DOI: 10.3892/ijmm.2018.3972] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 10/22/2018] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to explore the underlying mechanisms of bone morphogenetic protein 2 (BMP2) in alleviating intervertebral disc degeneration (IDD). A rat puncture IDD model was constructed, and the rats were randomly divided into six groups: Control; IDD (model); IDD+PBS [containing 1010 adeno‑associated virus serotype 2 (AAV)]; and IDD + AAV2‑BMP2 (106, 108 and 1010). IL‑1β was used to treat primary nucleus pulposus (NP) cells to mimic IDD in vitro. The effects of BMP2 in IDD were determined by magnetic resonance imaging (MRI), hematoxylin and eosin staining and Alcian Blue staining in vivo. The levels of collagen II, aggrecan, transcription factor SOX9 (SOX9) and matrix metalloproteinase 13 (MMP‑13) were examined using western blot analysis and reverse transcription quantitative polymerase chain reaction (RT‑qPCR) in NP tissues and cells. The expression of C‑telopeptide of type II collagen (CTX‑II) in the sera or cell supernatants was determined by ELISA. In addition, the levels of phosphorylation of phosphoinositide 3‑kinase (PI3K) and protein kinase B (Akt), and the levels of apoptosis‑associated proteins and apoptosis ratio of NP cells were also determined by western blot analysis and flow cytometry, respectively. LY29400, an inhibitor of PI3K, was used to additionally confirm the signal pathway mechanism of BMP2 treatment in IDD. BMP2 significantly extended the interval between discs and alleviated the fibrous ring rupture and the decrease in the levels of glycoproteins in IDD rats, as determined by MRI and histological staining. Additionally, BMP2 treatment significantly upregulated the levels of collagen II, aggrecan and SOX9, but downregulated the levels of MMP‑13 and CTX‑II in IDD rats and NP cells in a dose‑dependent manner. Concurrently, recombinant human (rh)BMP2 pretreatment also significantly decreased the apoptosis ratio of interleukin (IL)‑1β‑treated NP cells via downregulating the level of cleaved caspase‑3 and upregulating the level of uncleaved poly (adenosine 5'‑diphosphate‑ribose) polymerase. It was demonstrated that rhBMP2 also significantly decreased the inflammatory response in NP tissues and cells, based on levels of IL‑6, TNF‑α and IL‑10. In addition, rhBMP2 inhibited cell apoptosis via upregulating the phosphorylation levels of the PI3K/Akt signaling pathway, and LY29400 pretreatment inhibited the effects of BMP2 in IL‑1β treated NP cells. BMP2 alleviated IDD via the PI3K/Akt signaling pathway by inhibiting NP cell apoptosis and decreasing the levels of matrix proteins.
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Affiliation(s)
- Yanlin Tan
- Department of Spinal Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Xingwang Yao
- Department of Spinal Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Zhehao Dai
- Department of Spinal Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yunhua Wang
- Department of Positron Emission Tomography/Computed Tomography Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Guohua Lv
- Department of Spinal Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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