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1
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Ok MU, Şahin R, Balik MS, Okçu O. The healing effects of L-carnitine and spongostan on cartilage defect in rat model. Injury 2023; 54:111115. [PMID: 37867024 DOI: 10.1016/j.injury.2023.111115] [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: 05/01/2023] [Revised: 10/08/2023] [Accepted: 10/09/2023] [Indexed: 10/24/2023]
Abstract
PURPOSE We aimed to determine the effect of L-carnitine and spongostan on cartilage healing in an experimental animal model with a full-thickness cartilage defect. METHODS In the study 32 Sprague-Dawley rats were divided into four groups in equal numbers. A cartilage defect with a diameter of 1 mm and a depth of 3 mm was created in the femoral intercondylar region of rats in groups A, B, and C. Group A received no treatment in the defective area. Group B received treatment with spongostan. Group C received treatment with spongostan soaked in L-carnitine. Group D served as the healthy control group. The rats were euthanized 6 weeks after the treatment. Histological evaluation of the condyles was done with the modified Mankin scoring. RESULTS In the histopathological imaging of the cartilage structure, it was observed that in group A, there was complete disorganization and cellular structure was completely absent up to the subchondral bone. In group B, moderate structural improvement, partially intact appearance in border integrity and mostly diffuse hypercellularity were observed. In group C, a near-normal healing, a completely intact appearance in boundary integrities and normal or hypercellularity in cellular structure were observed. The total score of the modified Mankin decreases numerically from A to D. There was no statistically significant difference observed between the A-B (p = 0.176), C-D (p = 0.145), and C-B (p = 0.580) groups, while significant differences were detected between the A-C (p = 0.004), B-D (p = 0.007), and A-D (p = 0.000) groups. CONCLUSION It has been known that mitochondrial activity is reduced in the osteoarthritis, and as a result, decrease in cellular activity occurs with ATP synthesis. For this reason, we found that L-carnitine, which we expect to stimulate cell proliferation by stimulating ATP synthesis, makes a positive contribution to cartilage healing, as expected. It has been found that combining spongostan with L-carnitine for the treatment of cartilage healing, instead of applying spongostan alone, provides near-normal healing.
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Affiliation(s)
- Muhammet Uğur Ok
- Department of Orthopaedia and Traumatology, Bismil State Hospital, Diyarbakir, Turkey
| | - Rıfat Şahin
- Department of Orthopaedia and Traumatology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey.
| | - Mehmet Sabri Balik
- Department of Orthopaedia and Traumatology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
| | - Oğuzhan Okçu
- Department of Pathology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize, Turkey
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2
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Wen ZH, Sung CS, Lin SC, Yao ZK, Lai YC, Liu YW, Wu YY, Sun HW, Liu HT, Chen WF, Jean YH. Intra-Articular Lactate Dehydrogenase A Inhibitor Oxamate Reduces Experimental Osteoarthritis and Nociception in Rats via Possible Alteration of Glycolysis-Related Protein Expression in Cartilage Tissue. Int J Mol Sci 2023; 24:10770. [PMID: 37445948 DOI: 10.3390/ijms241310770] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/11/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Osteoarthritis (OA) is the most common form of arthritis and joint disorder worldwide. Metabolic reprogramming of osteoarthritic chondrocytes from oxidative phosphorylation to glycolysis results in the accumulation of lactate from glycolytic metabolite pyruvate by lactate dehydrogenase A (LDHA), leading to cartilage degeneration. In the present study, we investigated the protective effects of the intra-articular administration of oxamate (LDHA inhibitor) against OA development and glycolysis-related protein expression in experimental OA rats. The animals were randomly allocated into four groups: Sham, anterior cruciate ligament transection (ACLT), ACLT + oxamate (0.25 and 2.5 mg/kg). Oxamate-treated groups received an intra-articular injection of oxamate once a week for 5 weeks. Intra-articular oxamate significantly reduced the weight-bearing defects and knee width in ACLT rats. Histopathological analyses showed that oxamate caused significantly less cartilage degeneration in the ACLT rats. Oxamate exerts hypertrophic effects in articular cartilage chondrocytes by inhibiting glucose transporter 1, glucose transporter 3, hexokinase II, pyruvate kinase M2, pyruvate dehydrogenase kinases 1 and 2, pyruvate dehydrogenase kinase 2, and LHDA. Further analysis revealed that oxamate significantly reduced chondrocyte apoptosis in articular cartilage. Oxamate attenuates nociception, inflammation, cartilage degradation, and chondrocyte apoptosis and possibly attenuates glycolysis-related protein expression in ACLT-induced OA rats. The present findings will facilitate future research on LDHA inhibitors in prevention strategies for OA progression.
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Affiliation(s)
- Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Institute of BioPharmaceutical Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Chun-Sung Sung
- Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Sung-Chun Lin
- Department of Orthopedic Surgery, Pingtung Christian Hospital, No. 60 Dalian Road, Pingtung 90059, Taiwan
| | - Zhi-Kang Yao
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Orthopedic Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 81341, Taiwan
| | - Yu-Cheng Lai
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Orthopedics, Asia University Hospital, Taichung 41354, Taiwan
| | - Yu-Wei Liu
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Yu-Yan Wu
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Hsi-Wen Sun
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
| | - Hsin-Tzu Liu
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 97002, Taiwan
| | - Wu-Fu Chen
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833301, Taiwan
| | - Yen-Hsuan Jean
- Department of Orthopedic Surgery, Pingtung Christian Hospital, No. 60 Dalian Road, Pingtung 90059, Taiwan
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Sasaki E, Yamamoto H, Asari T, Matsuta R, Ota S, Kimura Y, Sasaki S, Ishibashi K, Yamamoto Y, Kami K, Ando M, Tsuda E, Ishibashi Y. Metabolomics with severity of radiographic knee osteoarthritis and early phase synovitis in middle-aged women from the Iwaki Health Promotion Project: a cross-sectional study. Arthritis Res Ther 2022; 24:145. [PMID: 35710532 PMCID: PMC9205107 DOI: 10.1186/s13075-022-02830-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 05/29/2022] [Indexed: 01/15/2023] Open
Abstract
Background Osteoarthritis (OA) is one of the costliest and most disabling forms of arthritis, and it poses a major public health burden; however, its detailed etiology, pathophysiology, and metabolism remain unclear. Therefore, the purpose of this study was to investigate the key plasma metabolites and metabolic pathways, especially focusing on radiographic OA severity and synovitis, from a large sample cohort study. Methods We recruited 596 female volunteers who participated in the Iwaki Health Promotion Project in 2017. Standing anterior-posterior radiographs of the knee were classified by the Kellgren-Lawrence (KL) grade. Radiographic OA was defined as a KL grade of ≥ 2. Individual effusion-synovitis was scored according to the Whole-Organ Magnetic Resonance Imaging Scoring System. Blood samples were collected, and metabolites were extracted from the plasma. Metabolome analysis was performed using capillary electrophoresis time-of-flight mass spectrometry. To investigate the relationships among metabolites, the KL grade, and effusion-synovitis scores, partial least squares with rank order of groups (PLS-ROG) analyses were performed. Results Among the 82 metabolites examined in this assay, PLS-ROG analysis identified 42 metabolites that correlated with OA severity. A subsequent metabolite set enrichment analysis using the significant metabolites showed the urea cycle and tricarboxylic acid cycle as key metabolic pathways. Moreover, further PLS-ROG analysis identified cystine (p = 0.009), uric acid (p = 0.024), and tyrosine (p = 0.048) as common metabolites associated with both OA severity and effusion-synovitis. Receiver operating characteristic analyses showed that cystine levels were moderately associated with radiographic OA (p < 0.001, area under the curve 0.714, odds ratio 3.7). Conclusion Large sample metabolome analyses revealed that cystine, an amino acid associated with antioxidant activity and glutamate homeostasis, might be a potential metabolic biomarker for radiographic osteoarthritis and early phase synovitis. Supplementary Information The online version contains supplementary material available at 10.1186/s13075-022-02830-w.
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Affiliation(s)
- Eiji Sasaki
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
| | - Hiroyuki Yamamoto
- Human Metabolome Technologies, Tsuruoka, Japan.,Department of Metabolomics Innovation, Hirosaki, Japan
| | - Toru Asari
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Rira Matsuta
- Human Metabolome Technologies, Tsuruoka, Japan.,Department of Metabolomics Innovation, Hirosaki, Japan
| | - Seiya Ota
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Yuka Kimura
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Shizuka Sasaki
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Kyota Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Yuji Yamamoto
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | | | - Masataka Ando
- School of Allied Health Sciences, Kitasato University, Kanagawa, Japan
| | - Eiichi Tsuda
- Department of Rehabilitation Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yasuyuki Ishibashi
- Department of Orthopaedic Surgery, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
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Liu Y, Zeng Y, Si HB, Tang L, Xie HQ, Shen B. Exosomes Derived From Human Urine-Derived Stem Cells Overexpressing miR-140-5p Alleviate Knee Osteoarthritis Through Downregulation of VEGFA in a Rat Model. Am J Sports Med 2022; 50:1088-1105. [PMID: 35179989 DOI: 10.1177/03635465221073991] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Knee osteoarthritis (KOA) is one of the most common chronic musculoskeletal disorders worldwide, for which exosomes derived from stem cells may provide an effective treatment. PURPOSE To assess the effect of exosomes derived from human urine-derived stem cells (hUSCs) overexpressing miR-140-5p (miR means microRNA) on KOA in an in vitro interleukin 1β (IL-1β)-induced osteoarthritis (OA) model and an in vivo rat KOA model. STUDY DESIGN Controlled laboratory study. METHODS Exosomes derived from hUSCs (hUSC-Exos) were isolated and validated. The hUSCs were transfected with miR-140s using lentivirus, and exosomes secreted from such cells (hUSC-140-Exos) were collected. The roles of hUSC-Exos and hUSC-140-Exos in protecting chondrocytes against IL-1β treatment were compared by analyzing the proliferation, migration, apoptosis, and secretion of extracellular matrix (ECM) in chondrocytes. After vascular endothelial growth factor A (VEGFA) was identified as a target of miR-140, the mechanism by which VEGFA can mediate the beneficial effect of miR-140 on OA was investigated using small interfering RNA transfection or chemical drugs. The expression of VEGFA in cartilage and synovial fluid from patients with KOA was measured and compared with that of healthy controls. Surgery for anterior cruciate ligament transection and destabilization of the medial meniscus were performed on the knee joints of Sprague-Dawley rats to establish an animal model of OA, and intra-articular (IA) injection of hUSC-Exos or hUSC-140-Exos was conducted at 4 to 8 weeks after the surgery. Cartilage regeneration and subchondral bone remodeling were evaluated through histological staining and micro-computed tomography analysis. RESULTS Proliferation and migration ability were enhanced and apoptosis was inhibited in chondrocytes treated with IL-1β via hUSC-Exos, with the side effect of decreased ECM secretion. hUSC-140-Exos not only retained the advantages of hUSC-Exos but also increased the secretion of ECM by targeting VEGFA, including collagen II and aggrecan. Increased expression of VEGFA during the progression of KOA was also confirmed in cartilage and synovial fluid samples obtained from patients with OA. In the rat OA model, IA injection of hUSC-140-Exos enhanced cartilage regeneration and subchondral bone remodeling. CONCLUSION Our results demonstrated the superiority of hUSC-Exos overexpressing miR-140-5p for treating OA compared with the hUSC-Exos. The effect of hUSC-140-Exos for suppressing the progression of KOA is in part mediated by VEGFA. CLINICAL RELEVANCE Exosomes derived from stem cells may provide a promising treatment for KOA, and our study can advance the related basic research.
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Affiliation(s)
- Yuan Liu
- Orthopedics Research Institute, Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Laboratory of Stem Cell and Tissue Engineering, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Zeng
- Orthopedics Research Institute, Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hai-Bo Si
- Orthopedics Research Institute, Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Li Tang
- Laboratory of Stem Cell and Tissue Engineering, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hui-Qi Xie
- Orthopedics Research Institute, Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.,Laboratory of Stem Cell and Tissue Engineering, Med-X Center for Materials, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bin Shen
- Orthopedics Research Institute, Department of Orthopedics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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5
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Jin Y, Xu M, Zhu H, Dong C, Ji J, Liu Y, Deng A, Gu Z. Therapeutic effects of bone marrow mesenchymal stem cells-derived exosomes on osteoarthritis. J Cell Mol Med 2021; 25:9281-9294. [PMID: 34448527 PMCID: PMC8500984 DOI: 10.1111/jcmm.16860] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/20/2021] [Accepted: 07/31/2021] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) have shown chondroprotective effects in clinical models of osteoarthritis (OA). However, effects of MSC‐derived exosomes on OA remain unclear. The study aimed to investigate the therapeutic potential of exosomes from human bone marrow MSCs (BM‐MSCs) in alleviating OA. The anterior cruciate ligament transection (ACLT) and destabilization of the medial meniscus (DMM) surgery were performed on the knee joints of a rat OA model, followed by intra‐articular injection of BM‐MSCs or their exosomes. In addition, BM‐MSC‐derived exosomes were administrated to primary human chondrocytes to observe the functional and molecular alterations. Both of BM‐MSCs and BM‐MSC‐derived exosomes alleviated cartilage destruction and subchondral bone remodelling in OA rat model. Administration of BM‐MSCs and exosomes could reduce joint damage and restore the trabecular bone volume fraction, trabecular number and connectivity density of OA rats. In addition, in vitro assays showed that BM‐MSCs‐exosomes could maintain the chondrocyte phenotype by increasing collagen type II synthesis and inhibiting IL‐1β–induced senescence and apoptosis. Furthermore, exosomal lncRNA MEG‐3 also reduced the senescence and apoptosis of chondrocytes induced by IL‐1β, indicating that lncRNA MEG‐3 might partially account the anti‐OA effects of BM‐MSC exosomes. The exosomes from BM‐MSCs exerted beneficial therapeutic effects on OA by reducing the senescence and apoptosis of chondrocytes, suggesting that MSC‐derived exosomes might provide a candidate therapy for OA treatment.
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Affiliation(s)
- Yi Jin
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China.,Medical School, Nantong University, Nantong, China
| | - Min Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, China
| | - Hai Zhu
- Department of Orthopaedics, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, China
| | - Chen Dong
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China.,Medical School, Nantong University, Nantong, China
| | - Juan Ji
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yake Liu
- Department of Orthopaedics, Affiliated Hospital of Nantong University, Nantong, China
| | - Aidong Deng
- Department of Hand surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Zhifeng Gu
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, China
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Lokhnauth J, Driscoll KE, Bendele A, Niazi F, Liang A, Larsen CC. Viscosupplementation may preserve tibial cartilage and collagen in osteoarthritis: findings from a preclinical model of osteoarthritis. J Exp Orthop 2020; 7:39. [PMID: 32476071 PMCID: PMC7261714 DOI: 10.1186/s40634-020-00256-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/20/2020] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Intraarticular (IA) hyaluronic acid (HA) injection is used to reduce pain and improve mobility in knee osteoarthritis (OA). Little is known about histopathological changes underlying HA efficacy. This study investigated dose-related effects of 1% sodium hyaluronate (BioHA) on knee joint histopathology and pain responses in a medial meniscal tear (MMT) rat model of OA. METHODS Following MMT surgery, rats were randomized into treatment groups: single IA injection of vehicle, BioHA, or an avian-derived hyaluronic acid (hylan G-F 20) on Day 7; or 3 weekly injections of vehicle or BioHA on Days 7, 14, and 21. On Day 35, joints were evaluated by microscopic histopathology for cartilage degeneration, collagen degeneration, synovitis, and cytokine expression (tumor necrosis factor α, transforming growth factor β). RESULTS Joint pathology for control animals was consistent with that expected for the MMT model. Rats treated with 3 injections of IA-BioHA had significantly reduced collagen degeneration (21%) relative to control animals. No significant change in collagen degeneration was observed for rats given a single injection of hylan G-F 20 or IA-BioHA compared to control animals. HA treatment did not affect cytokine expression. CONCLUSIONS IA-BioHA viscosupplementation in a rat MMT model of OA showed preservation of joint cartilage and collagen. This effect was most pronounced on tibial surfaces having less severe injury, suggesting that treatment should be initiated early in the disease process. A comparison of responses to IA-BioHA or hylan G-F 20 in the MMT rat OA model suggest IA-BioHA may be more effective in preserving joint connective tissue.
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Affiliation(s)
- John Lokhnauth
- Ferring Pharmaceuticals Inc., 100 Interpace Parkway, Parsippany, NJ, 07054, USA.
| | | | | | - Faizan Niazi
- Ferring Pharmaceuticals Inc., 100 Interpace Parkway, Parsippany, NJ, 07054, USA
| | - Alfred Liang
- Ferring Pharmaceuticals Inc., 100 Interpace Parkway, Parsippany, NJ, 07054, USA
| | - Crilles C Larsen
- Ferring Pharmaceuticals Inc., 100 Interpace Parkway, Parsippany, NJ, 07054, USA
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7
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Shin K, Cha Y, Ban YH, Seo DW, Choi EK, Park D, Kang SK, Ra JC, Kim YB. Anti-osteoarthritis effect of a combination treatment with human adipose tissue-derived mesenchymal stem cells and thrombospondin 2 in rabbits. World J Stem Cells 2019; 11:1115-1129. [PMID: 31875872 PMCID: PMC6904861 DOI: 10.4252/wjsc.v11.i12.1115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 10/14/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteoarthritis (OA), a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage, is one of the leading causes of disability. As a new strategy for treatment of OA, mesenchymal stem cells (MSCs) have the potential for articular cartilage regeneration. Meanwhile, thrombospondin 2 (TSP2) promotes the chondrogenic differentiation of MSCs. AIM To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs (hADMSCs) and potentiates the therapeutic effects of hADMSCs in OA rabbits. METHODS We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA (siRNA)-treated stem cells. Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits, and 8 wk later, hADMSCs (1.7 × 106 or 1.7 × 107 cells) were injected into the injured knees alone or in combination with intra-articular injection of TSP2 (100 ng/knee) at 2-d intervals. OA progression was monitored by gross, radiological, and histological examinations. RESULTS In hADMSC culture, treatment with TSP2 increased the expression of chondrogenic markers (SOX9 and collagen II) as well as NOTCH signaling genes (JAGGED1 and NOTCH3), which were inhibited by TSP2 siRNA treatment. In vivo, OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration, osteophyte formation, and extracellular matrix loss 8 wk after cell transplantation. Notably, such cartilage damage was further alleviated by the combination of hADMSCs and TSP2. In addition, synovial inflammatory cytokines, especially tumor-necrosis factor-α, markedly decreased following the combination treatment. CONCLUSION The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs via JAGGED1/NOTCH3 signaling, and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.
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Affiliation(s)
- Kyungha Shin
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Yeseul Cha
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Young-Hwan Ban
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Da Woom Seo
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Ehn-Kyoung Choi
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
| | - Dongsun Park
- Department of Biology Education, Korea National University of Education, Cheongju 28173, Chungbuk, South Korea
| | - Sung Keun Kang
- Biostar Stem Cell Research Institute, R-BIO Co., Ltd., Seoul 07238, South Korea
| | - Jeong Chan Ra
- Biostar Stem Cell Research Institute, R-BIO Co., Ltd., Seoul 07238, South Korea
| | - Yun-Bae Kim
- College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea.
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8
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miR-140 Attenuates the Progression of Early-Stage Osteoarthritis by Retarding Chondrocyte Senescence. MOLECULAR THERAPY-NUCLEIC ACIDS 2019; 19:15-30. [PMID: 31790972 PMCID: PMC6909049 DOI: 10.1016/j.omtn.2019.10.032] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 09/01/2019] [Accepted: 10/25/2019] [Indexed: 02/05/2023]
Abstract
Osteoarthritis (OA) is a major cause of joint pain and disability, and chondrocyte senescence is a key pathological process in OA and may be a target of new therapeutics. MicroRNA-140 (miR-140) plays a protective role in OA, but little is known about its epigenetic effect on chondrocyte senescence. In this study, we first validated the features of chondrocyte senescence characterized by increased cell cycle arrest in the G0/G1 phase and the expression of senescence-associated β-galactosidase (SA-βGal), p16INK4a, p21, p53, and γH2AX in human knee OA. Then, we revealed in interleukin 1β (IL-1β)-induced OA chondrocytes in vitro that pretransfection with miR-140 effectively inhibited the expression of SA-βGal, p16INK4a, p21, p53, and γH2AX. Furthermore, in vivo results from trauma-induced early-stage OA rats showed that intra-articularly injected miR-140 could rapidly reach the chondrocyte cytoplasm and induce molecular changes similar to the in vitro results, resulting in a noticeable alleviation of OA progression. Finally, bioinformatics analysis predicted the potential targets of miR-140 and a mechanistic network by which miR-140 regulates chondrocyte senescence. Collectively, miR-140 can effectively attenuate the progression of early-stage OA by retarding chondrocyte senescence, contributing new evidence of the involvement of miR-mediated epigenetic regulation of chondrocyte senescence in OA pathogenesis.
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Rotter Sopasakis V, Wickelgren R, Sukonina V, Brantsing C, Svala E, Hansson E, Enerbäck S, Lindahl A, Skiöldebrand E. Elevated Glucose Levels Preserve Glucose Uptake, Hyaluronan Production, and Low Glutamate Release Following Interleukin-1β Stimulation of Differentiated Chondrocytes. Cartilage 2019; 10:491-503. [PMID: 29701083 PMCID: PMC6755873 DOI: 10.1177/1947603518770256] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Chondrocytes are responsible for remodeling and maintaining the structural and functional integrity of the cartilage extracellular matrix. Because of the absence of a vascular supply, chondrocytes survive in a relatively hypoxic environment and thus have limited regenerative capacity during conditions of cellular stress associated with inflammation and matrix degradation, such as osteoarthritis (OA). Glucose is essential to sustain chondrocyte metabolism and is a precursor for key matrix components. In this study, we investigated the importance of glucose as a fuel source for matrix repair during inflammation as well as the effect of glucose on inflammatory mediators associated with osteoarthritis. DESIGN To create an OA model, we used equine chondrocytes from 4 individual horses that were differentiated into cartilage pellets in vitro followed by interleukin-1β (IL-1β) stimulation for 72 hours. The cells were kept at either normoglycemic conditions (5 mM glucose) or supraphysiological glucose concentrations (25 mM glucose) during the stimulation with IL-1β. RESULTS We found that elevated glucose levels preserve glucose uptake, hyaluronan synthesis, and matrix integrity, as well as induce anti-inflammatory actions by maintaining low expression of Toll-like receptor-4 and low secretion of glutamate. CONCLUSIONS Adequate supply of glucose to chondrocytes during conditions of inflammation and matrix degradation interrupts the detrimental inflammatory cycle and induces synthesis of hyaluronan, thereby promoting cartilage repair.
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Affiliation(s)
- Victoria Rotter Sopasakis
- Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden,Victoria Rotter Sopasakis, Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska Academy, University of Gothenburg, Bruna Stråket 16, SE-413 45 Gothenburg, Sweden.
| | - Ruth Wickelgren
- Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Valentina Sukonina
- Department of Medical Biochemistry and Cell biology, University of Gothenburg, Gothenburg, Sweden
| | - Camilla Brantsing
- Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Emilia Svala
- Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Gothenburg, Sweden
| | - Elisabeth Hansson
- Department of Clinical Neuroscience, University of Gothenburg, Gothenburg, Sweden
| | - Sven Enerbäck
- Department of Medical Biochemistry and Cell biology, University of Gothenburg, Gothenburg, Sweden
| | - Anders Lindahl
- Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Eva Skiöldebrand
- Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden
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10
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Altman R, Bedi A, Manjoo A, Niazi F, Shaw P, Mease P. Anti-Inflammatory Effects of Intra-Articular Hyaluronic Acid: A Systematic Review. Cartilage 2019; 10:43-52. [PMID: 29429372 PMCID: PMC6376563 DOI: 10.1177/1947603517749919] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE Osteoarthritis (OA) is one of the leading causes of disability in the adult population. Common nonoperative treatment options include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular corticosteroids, and intra-articular injections of hyaluronic acid (HA). HA is found intrinsically within the knee joint providing viscoelastic properties to the synovial fluid. HA therapy provides anti-inflammatory relief through a number of different pathways, including the suppression of pro-inflammatory cytokines and chemokines. METHODS We conducted a systematic review to summarize the published literature on the anti-inflammatory properties of hyaluronic acid in osteoarthritis. Included articles were categorized based on the primary anti-inflammatory responses described within them, by the immediate cell surface receptor protein assessed within the article, or based on the primary theme of the article. Key findings aimed to describe the macromolecules and inflammatory-mediated responses associated with the cell transmembrane receptors. RESULTS Forty-eight articles were included in this systematic review that focused on the general anti-inflammatory effects of HA in knee OA, mediated through receptor-binding relationships with cluster determinant 44 (CD44), toll-like receptor 2 (TLR-2) and 4 (TLR-4), intercellular adhesion molecule-1 (ICAM-1), and layilin (LAYN) cell surface receptors. Higher molecular weight HA (HMWHA) promotes anti-inflammatory responses, whereas short HA oligosaccharides produce inflammatory reactions. CONCLUSIONS Intra-articular HA is a viable therapeutic option in treating knee OA and suppressing inflammatory responses. HMWHA is effective in suppressing the key macromolecules that elicit the inflammatory response by short HA oligosaccharides.
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Affiliation(s)
- Roy Altman
- Division of Rheumatology and Immunology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA,Roy Altman, 9854 West Bald Mountain Court, Santa Clarita, CA 91390, USA.
| | - Asheesh Bedi
- Chief of Sports Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA
| | - Ajay Manjoo
- Department of Orthopedics, McMaster University, Hamilton, Ontario, Canada
| | - Faizan Niazi
- Ferring Pharmaceuticals Inc., Parsippany, NJ, USA
| | - Peter Shaw
- Ferring Pharmaceuticals Inc., Parsippany, NJ, USA
| | - Philip Mease
- Swedish-Providence-St. Joseph’s Health Systems, Seattle, WA, USA,University of Washington School of Medicine, Seattle, WA, USA
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11
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Zhang FX, Ge SN, Dong YL, Shi J, Feng YP, Li Y, Li YQ, Li JL. Vesicular glutamate transporter isoforms: The essential players in the somatosensory systems. Prog Neurobiol 2018; 171:72-89. [PMID: 30273635 DOI: 10.1016/j.pneurobio.2018.09.006] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 08/28/2018] [Accepted: 09/23/2018] [Indexed: 02/08/2023]
Abstract
In nervous system, glutamate transmission is crucial for centripetal conveyance and cortical perception of sensory signals of different modalities, which necessitates vesicular glutamate transporters 1-3 (VGLUT 1-3), the three homologous membrane-bound protein isoforms, to load glutamate into the presysnaptic vesicles. These VGLUTs, especially VGLUT1 and VGLUT2, selectively label and define functionally distinct neuronal subpopulations at each relay level of the neural hierarchies comprising spinal and trigeminal sensory systems. In this review, by scrutinizing each structure of the organism's fundamental hierarchies including dorsal root/trigeminal ganglia, spinal dorsal horn/trigeminal sensory nuclear complex, somatosensory thalamic nuclei and primary somatosensory cortex, we summarize and characterize in detail within each relay the neuronal clusters expressing distinct VGLUT protein/transcript isoforms, with respect to their regional distribution features (complementary distribution in some structures), axonal terminations/peripheral innervations and physiological functions. Equally important, the distribution pattern and characteristics of VGLUT1/VGLUT2 axon terminals within these structures are also epitomized. Finally, the correlation of a particular VGLUT isoform and its physiological role, disclosed thus far largely via studying the peripheral receptors, is generalized by referring to reports on global and conditioned VGLUT-knockout mice. Also, researches on VGLUTs relating to future direction are tentatively proposed, such as unveiling the elusive differences between distinct VGLUTs in mechanism and/or pharmacokinetics at ionic/molecular level, and developing VGLUT-based pain killers.
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Affiliation(s)
- Fu-Xing Zhang
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China
| | - Shun-Nan Ge
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China; Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China
| | - Yu-Lin Dong
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China
| | - Juan Shi
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China
| | - Yu-Peng Feng
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China
| | - Yang Li
- Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an 710038, PR China
| | - Yun-Qing Li
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China; Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, PR China.
| | - Jin-Lian Li
- Department of Anatomy and K.K. Leung Brain Research Centre, School of Basic Medicine, The Fourth Military Medical University, Xi'an 710032, PR China.
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12
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Abstract
Objective Summarize the biologic effects of Supartz FX for knee osteoarthritis (OA), the first worldwide clinically approved intra-articular (IA) hyaluronic acid (HA) product. Design To determine the mechanism of action from preclinical and clinical studies, a literature search was conducted of Supartz FX using academic databases from 1987 to 2016. Articles on Supartz FX that deal with its mechanisms of action were extracted, categorized, and reviewed. Results Supartz FX has 2 potential mechanisms of action: (1) biomechanical: IA Supartz FX directly improves the viscoelasticity and lubrication of synovial fluid; (2) physiologic: IA Supartz FX penetrates synovium and cartilage tissues to reach HA receptors on the surface of synoviocytes and chondrocytes. In synovium, suppression of gene expression in inflammatory mediators results in improved endogenous HA production, improved properties of synovial fluid, and reduction in pain. In cartilage, suppression of gene expression of collagenases and aggrecanases suppresses cartilage degeneration. Conclusion The net results of basic and clinical studies is that IA Supartz FX provides a more favorable biomechanical and functional environment in the knee joint. Hence, it is not only a lubricant but is also physiologically active. These actions may help explain both short- and long-term improvement in pain and function often achieved from IA Supartz FX in knee OA.
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Affiliation(s)
- Roy D. Altman
- Department of Medicine, Division of Rheumatology and Immunology, David Geffen School of Medicine, University of California Los Angeles, CA, USA,Roy D. Altman, Division of Rheumatology and Immunology, David Geffen School of Medicine, University of California at Los Angeles, 1000 Veterans Ave, Los Angeles 90024, CA, USA.
| | - Vinod Dasa
- Department of Orthopaedics, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Jun Takeuchi
- Pharmaceuticals Information Group, Seikagaku Corporation, Tokyo, Japan
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13
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Si HB, Zeng Y, Liu SY, Zhou ZK, Chen YN, Cheng JQ, Lu YR, Shen B. Intra-articular injection of microRNA-140 (miRNA-140) alleviates osteoarthritis (OA) progression by modulating extracellular matrix (ECM) homeostasis in rats. Osteoarthritis Cartilage 2017. [PMID: 28647469 DOI: 10.1016/j.joca.2017.06.002] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Disruptions of extracellular matrix (ECM) homeostasis are key events in the pathogenesis of osteoarthritis (OA). MicroRNA-140 (miRNA-140) is expressed specifically in cartilage and regulates ECM-degrading enzymes. Our objective in this study was to determine if intra-articular injection of miRNA-140 can attenuate OA progression in rats. DESIGN miRNA-140 levels in human normal and OA cartilage derived chondrocytes and synovial fluid were assessed by polymerase chain reaction (PCR). After primary human chondrocytes were transfected with miRNA-140 mimic or inhibitor, PCR and western blotting were performed to quantify Collagen II, MMP-13, and ADAMTS-5 expression. An OA model was induced surgically in rats, and subsequently treated with one single intra-articular injection of miRNA-140 agomir. At 4, 8, and 12 weeks after surgery, OA progression were evaluated macroscopically, histologically, and immunohistochemically in these rats. RESULTS miRNA-140 levels were significantly reduced in human OA cartilage derived chondrocytes and synovial fluid compared with normal chondrocytes and synovial fluid. Overexpressing miRNA-140 in primary human chondrocytes promoted Collagen II expression and inhibited MMP-13 and ADAMTS-5 expression. miRNA-140 levels in rat cartilage were significantly higher in the miRNA-140 agomir group than in the control group. Moreover, behavioural scores, chondrocyte numbers, cartilage thickness and Collagen II expression levels in cartilage were significantly higher, while pathological scores and MMP-13 and ADAMTS-5 expression levels were significantly lower in the miRNA-140 agomir group than in the control group. CONCLUSION Intra-articular injection of miRNA-140 can alleviate OA progression by modulating ECM homeostasis in rats, and may have potential as a new therapy for OA.
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Affiliation(s)
- H-B Si
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
| | - Y Zeng
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China.
| | - S-Y Liu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
| | - Z-K Zhou
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China.
| | - Y-N Chen
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
| | - J-Q Cheng
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
| | - Y-R Lu
- Key Laboratory of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, China.
| | - B Shen
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China.
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14
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Chang NJ, Lee KW, Chu CJ, Shie MY, Chou PH, Lin CC, Liang PI. A Preclinical Assessment of Early Continuous Passive Motion and Treadmill Therapeutic Exercises for Generating Chondroprotective Effects After Anterior Cruciate Ligament Rupture. Am J Sports Med 2017; 45:2284-2293. [PMID: 28520463 DOI: 10.1177/0363546517704847] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Anterior cruciate ligament (ACL) injury is a well-known risk factor for the development of posttraumatic osteoarthritis (PTOA). However, whether using continuous passive motion (CPM) with or without additional treadmill exercise (TRE) in early ACL injury might provide chondroprotective effects and further decrease the risk of PTOA has yet to be determined. HYPOTHESIS CPM may offer an enhanced chondroprotective effect, but TRE may attenuate that effect due to the mechanical stress on the joint and inflammatory cytokines in the joint. STUDY DESIGN Controlled laboratory study. METHODS Thirty adult New Zealand White male rabbits were randomly allocated to sedentary (SED), CPM, TRE, or CPM+TRE groups. Each rabbit underwent an ACL transection (ACLT) on the right knee, with the contralateral knee used as an internal control (sham). The 4 joint surfaces (ie, medial and lateral femoral condyles and tibial plateaus) were evaluated 4 weeks after surgery for gross appearance, histological characteristics, and quantitative osteoarthritis (OA) scores. RESULTS Overall, at the end of testing, the CPM group experienced the best protective therapeutic effects in all compartments. In gross appearance, CPM resulted in normal articular surfaces, while the TRE and SED groups exhibited surface abrasion. Histological analysis showed significant differences in articular cartilage status. The CPM group had significantly better histological OA scores ( P < .01), corresponding to the smoothest cartilage surface and sound chondrocyte and collagen arrangement. This group also showed abundant glycosaminoglycan (GAG) content and a sound growth microenvironment, with significantly lower expression levels of the inflammatory cytokine tumor necrosis factor α and the apoptotic marker caspase 3. In contrast, the TRE and SED groups showed several features of damage: distinct graded cartilage abrasion; damaged collagen fibers, corresponding to noticeable collagen type X (osteoarthritic cartilage); reduced cartilage thickness; fewer cartilaginous cells; and the appearance of chondrocyte clusters. These groups also showed loss of GAG, corresponding to higher levels of inflammatory cytokines and apoptosis of articular chondrocytes. Furthermore, the CPM+TRE group displayed visible pathological changes in the superficial cartilage, indicating that early loading exercise may contribute to osteoarthritis. The sham treatment showed no difference in the changes in all compartments between groups. CONCLUSION Immediate CPM therapy produces a superior in situ microenvironment for reducing the occurrence of PTOA after ACL injury without reconstruction in rabbits. CLINICAL RELEVANCE These data suggest that immediate application of CPM therapy may be necessary to create a sound microenvironment in joints and possibly to decrease the risk of PTOA without or while awaiting ACL reconstruction. In contrast, both early active loading exercise and inactivity lead to the development of PTOA.
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Affiliation(s)
- Nai-Jen Chang
- Department of Sports Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Kuan-Wei Lee
- Department of Sports Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Chih-Jou Chu
- Department of Sports Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Ming-You Shie
- 3D Printing Medical Research Center, China Medical University Hospital, North District, Taichung City, Taiwan
| | - Pei-Hsi Chou
- Department of Sports Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan
| | - Chih-Chan Lin
- Laboratory Animal Center, Department of Medical Research, Chi-Mei Medical Center, Yongkang District, Tainan City, Taiwan
| | - Peir-In Liang
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung City, Taiwan
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15
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Isaka S, Someya A, Nakamura S, Naito K, Nozawa M, Inoue N, Sugihara F, Nagaoka I, Kaneko K. Evaluation of the effect of oral administration of collagen peptides on an experimental rat osteoarthritis model. Exp Ther Med 2017; 13:2699-2706. [PMID: 28587333 PMCID: PMC5450616 DOI: 10.3892/etm.2017.4310] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 01/26/2017] [Indexed: 11/05/2022] Open
Abstract
Collagen is an extracellular matrix protein present in the skin, tendon, cartilage and bone. Collagen peptides (CP) are produced by the hydrolysis of gelatin (heat-denatured collagen) by proteases and are utilized as a component of nutraceuticals. The current study investigated the effect of CP on the articular cartilage of OA by evaluating the serum levels of biomarkers (CTX-II for type II collagen degradation and CPII for type II collagen synthesis), histopathological changes (Mankin score, based on the toluidine blue staining of proteoglycans), and immunohistochemical staining of matrix metalloproteinase (MMP)-13 and type II collagen, using a rat experimental osteoarthritis (OA) model. Anterior cruciate ligament transection (ACLT) was performed on the right knee joint to surgically induce OA. Animals were divided into four groups: Control group (Control), sham-operated group (Sham), ACLT group without collagen peptide (ACLT group) and ACLT group with oral administration of CP (CP group). ACLT induced histological damages and significantly increased the Mankin score (P<0.05). However, CP administration markedly suppressed the Mankin score, although this difference was not significant. In addition, serum CTX-II levels were significantly decreased in CP group compared with those in the ACLT group (P<0.05). By contrast, serum CPII levels did not differ significantly among the four groups. Moreover, immunohistochemical staining of type II collagen and MMP-13 (an important type II collagen-degrading enzyme) indicated that the amount of type II collagen increased, whereas the number of MMP-13 positive chondrocytes decreased in the CP group compared with ACLT group. These observations suggest that CP has the potential to exert chondroprotective action on OA by inhibiting MMP-13 expression and type II collagen degeneration.
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Affiliation(s)
- Satoko Isaka
- Department of Medicine for Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.,Department of Orthopaedic Surgery, Juntendo University, Nerima Hospital, Tokyo 117-8521, Japan
| | - Akimasa Someya
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Shinji Nakamura
- Laboratory of Morphology and Image Analysis, Biomedical Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kiyohito Naito
- Department of Medicine for Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Masahiko Nozawa
- Department of Medicine for Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan.,Department of Orthopaedic Surgery, Juntendo University, Nerima Hospital, Tokyo 117-8521, Japan
| | | | | | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kazuo Kaneko
- Department of Medicine for Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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16
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Yanagisawa K, Muneta T, Ozeki N, Nakagawa Y, Udo M, Saito R, Koga H, Tsuji K, Sekiya I. Weekly injections of Hylan G-F 20 delay cartilage degeneration in partial meniscectomized rat knees. BMC Musculoskelet Disord 2016; 17:188. [PMID: 27118194 PMCID: PMC4847373 DOI: 10.1186/s12891-016-1051-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 04/22/2016] [Indexed: 12/01/2022] Open
Abstract
Background Cross-linked hyaluronan—also called Hylan G-F 20—is a medical device developed to treat osteoarthritis of the knee. However, it is still controversial whether Hylan G-F 20 has a cartilage protective effect in trauma-induced osteoarthritis. We investigated whether Hylan G-F 20 delayed osteoarthritis progression in a partial meniscectomized rat model. Methods Lewis rats were used for the experiments. The anterior medial meniscus was resected at the level of the medial collateral ligament in both knees. From 1 week after the surgery, 50 μl of Hylan G-F 20 was injected weekly into the left knee and phosphate buffered saline was injected into the right knee. Cartilage was evaluated for macroscopic findings, histology with safranin-o, and expression of type II collagen at 2, 4, and 8 weeks. Synovitis was also evaluated, and immunohistochemical analysis was performed for ED1. Results Macroscopic findings demonstrated that India ink positive area, representing fibrillated cartilage, was significantly smaller in the Hylan G-F 20 group than in the control group at 2, 4, and 8 weeks (n = 5). There were no significant differences in osteophyte score between the Hylan G-F 20 group and the control group at 2, 4, and 8 weeks. Histologically, the cartilage in the medial tibial plateau was destroyed at 8 weeks in the control group, while type II collagen expression was still observed at 8 weeks in the Hylan G-F 20 group. OARSI score for cartilage histology was significantly lower in the Hylan G-F 20 group than in the control group at 4 and 8 weeks (n = 5). There were no significant differences in synovial cell number or modified synovitis score between the Hylan G-F 20 group and the control group at 2, 4, and 8 weeks (n = 5). In the Hylan G-F 20 group, foreign bodies surrounded by ED1 positive macrophages were observed in the synovium. Conclusion Weekly injections of Hylan G-F 20 starting 1 week after surgery delayed cartilage degeneration after meniscectomy in a rat model. Synovitis induced by meniscectomy was not alleviated by Hylan G-F 20. Insoluble gels were observed in the synovium after the Hylan G-F 20 injection.
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Affiliation(s)
- Katsuaki Yanagisawa
- Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Takeshi Muneta
- Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Nobutake Ozeki
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan
| | - Yusuke Nakagawa
- Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Mio Udo
- Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Ryusuke Saito
- Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Hideyuki Koga
- Department of Joint Surgery and Sports Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Kunikazu Tsuji
- Department of Cartilage Regeneration, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan
| | - Ichiro Sekiya
- Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
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17
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Tsai WY, Tsai RY, Liu CC, Wu JL, Wong CS. Sulfasalazine attenuates ACL transection and medial menisectomy-induced cartilage destruction by inhibition of cystine/glutamate antiporter. J Orthop Res 2016; 34:650-7. [PMID: 26466556 DOI: 10.1002/jor.23069] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Accepted: 10/06/2015] [Indexed: 02/04/2023]
Abstract
We had previously demonstrated that excitatory amino acid glutamate plays a role in the progression and severity of knee osteoarthritis (OA), and early hyaluronic acid injection attenuates the OA progression by attenuation of knee joint glutamate level, which was also related to the cystine/glutamate antiporter system X (system XC-) expression. System XC- uptakes cystine into chondrocytes for glutathione (GSH) synthesis, but the role of system XC- in OA is rarely addressed. Sulfasalazine (SSZ) is a system XC- inhibitor; SSZ was applied intra-articularly to study the function of system XC- in the development of OA in rats subjected to anterior cruciate ligament transection and medial meniscectomy (ACLT + MMx). Moerover, the system XC- activator N-acetylcysteine (NAC) was also applied to verify the role of system XC-. The intra-articular injection of SSZ significantly attenuated knee swelling and cartilage destruction in the knees of ACLT + MMx rats and this effect was blocked by NAC. The results showed that inhibition of system XC- function can attenuate ACLT + MMx-induced cartilage destruction. In the present study, system XC- inhibitor SSZ was shown to reduce glutamate content in synovial fluid and GSH in chondrocytes. It was also showed SSZ could attenuate ACLT + MMx-induced cartilage destruction, and treatment of NAC reversed the protective effect of SSZ.
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Affiliation(s)
- Wei-Yuan Tsai
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Ru-Yin Tsai
- Department of Nursing, Da-Yeh University, Changhua, Taiwan
| | - Chih-Chung Liu
- Institute of Systems Biology and Bioinformatics, National Central University, Zhongli, Taiwan.,Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan
| | - Jia-Lin Wu
- Department of Orthopaedics, Taipei Medical University, Taipei, Taiwan.,Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chih-Shung Wong
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan.,Neuropathic Pain and Translational Medicine Research Laboratory, Cathay General Hospital, Taipei, Taiwan.,School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan.,Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
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18
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Lewis R, Barrett-Jolley R. Changes in Membrane Receptors and Ion Channels as Potential Biomarkers for Osteoarthritis. Front Physiol 2015; 6:357. [PMID: 26648874 PMCID: PMC4664663 DOI: 10.3389/fphys.2015.00357] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 11/11/2015] [Indexed: 01/01/2023] Open
Abstract
Osteoarthritis (OA), a degenerative joint condition, is currently difficult to detect early enough for any of the current treatment options to be completely successful. Early diagnosis of this disease could increase the numbers of patients who are able to slow its progression. There are now several diseases where membrane protein biomarkers are used for early diagnosis. The numbers of proteins in the membrane is vast and so it is a rich source of potential biomarkers for OA but we need more knowledge of these before they can be considered practical biomarkers. How are they best measured and are they selective to OA or even certain types of OA? The first step in this process is to identify membrane proteins that change in OA. Here, we summarize several ion channels and receptors that change in OA models and/or OA patients, and may thus be considered candidates as novel membrane biomarkers of OA.
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Affiliation(s)
- Rebecca Lewis
- Faculty of Health and Medical Sciences, School of Veterinary Medicine and Science, University of Surrey Guildford, UK
| | - Richard Barrett-Jolley
- Department of Musculoskeletal Biology, Faculty of Health and Life Sciences, Institute of Ageing and Chronic Disease, University of Liverpool Liverpool, UK
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19
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Wen ZH, Chang YC, Jean YH. Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. Osteoarthritis Cartilage 2015; 23:2009-16. [PMID: 26521747 DOI: 10.1016/j.joca.2015.03.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 03/15/2015] [Accepted: 03/18/2015] [Indexed: 02/02/2023]
Abstract
Although a large proportion of patients with osteoarthritis (OA) show inflammation in their affected joints, the pathological role of inflammation in the development and progression of OA has yet to be clarified. Glutamate is considered an excitatory amino acid (EAA) neurotransmitter in the mammalian central nervous system (CNS). There are cellular membrane glutamate receptors and transporters for signal input modulation and termination as well as vesicular glutamate transporters (VGLUTs) for signal output through exocytotic release. Glutamate been shown to mediate intercellular communications in bone cells in a manner similar to synaptic transmission within the CNS. Glutamate-mediated events may also contribute to the pathogenesis and ongoing processes of peripheral nociceptive transduction and inflammation of experimental arthritis models as well as human arthritic conditions. This review will discuss the differential roles of glutamate signaling and blockade in peripheral neuronal and non-neuronal joint tissues, including bone remodeling systems and their potentials to impact OA-related inflammation and progression. This will serve to identify several potential targets to direct novel therapies for OA. Future studies will further elucidate the role of glutamate in the development and progression of OA, as well as its association with the clinical features of the disease.
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Affiliation(s)
- Z-H Wen
- Marine Biomedical Laboratory & Center for Translational Biopharmaceuticals, Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Taiwan
| | - Y-C Chang
- Marine Biomedical Laboratory & Center for Translational Biopharmaceuticals, Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Taiwan
| | - Y-H Jean
- Department of Orthopedic Surgery, Pingtung Christian Hospital, Pingtung, Taiwan.
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Gharbia O, Elmoaty Afify A, El Ghaffar HA, El Bassiony S, El Hawary AK, Lotfy A, Elsayed A, Mahmoud AA, Youssef A. The regenerative effect of human umbilical cord blood mesenchymal stem cells in a rabbit model of osteoarthritis. EGYPTIAN RHEUMATOLOGY AND REHABILITATION 2015. [DOI: 10.4103/1110-161x.168151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Abstract
Knee osteoarthritis (KOA) is the most common degenerative arthritis and is treated by a wide range of practitioners. Treatment planning requires knowledge of the knee joint components and the influence of systemic and environmental factors. The treatment of KOA has changed little in 50 years. We are entering a new stage where KOA is now being viewed as an organ in failure. Neurotransmission of pain is both peripheral and central. Medical treatment can influence both pathways. Current guidelines for treatment have more rigid criteria based on the literature. In the future, the use of genetic-based biomarkers, clinical patterns of response and imaging characteristics will likely create subgroups of individuals who could benefit from improved designer therapies.
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Affiliation(s)
- Fred Rt Nelson
- Emeritus, Department of Orthopaedics, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA;
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The Relationship between Anterior Cruciate Ligament Injury and Osteoarthritis of the Knee. Adv Orthop 2015; 2015:928301. [PMID: 25954533 PMCID: PMC4410751 DOI: 10.1155/2015/928301] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 01/22/2015] [Accepted: 01/22/2015] [Indexed: 12/18/2022] Open
Abstract
Anterior cruciate ligament (ACL) tears are a common injury, particularly in the athletic and youth populations. The known association between ACL injury and subsequent osteoarthritis (OA) of the knee merits a more in-depth understanding of the relationship between the ACL-injured knee and osteoarthritis. ACL injury, especially with concomitant meniscal or other ligamentous pathology, predisposes the knee to an increased risk of osteoarthritis. ACL insufficiency results in deterioration of the normal physiologic knee bending culminating in increased anterior tibial translation and increased internal tibial rotation. This leads to increased mean contact stresses in the posterior medial and lateral compartments under anterior and rotational loading. However, surgical reconstruction of the ACL has not been shown to reduce the risk of future OA development back to baseline and has variability based on operative factors of graft choice, timing of surgery, presence of meniscal and chondral abnormalities, and surgical technique. Known strategies to prevent OA development are applicable to patients with ACL deficiency or after ACL reconstruction and include weight management, avoidance of excessive musculoskeletal loading, and strength training. Reconstruction of the ACL does not necessarily prevent osteoarthritis in many of these patients and may depend on several external variables.
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Wen ZH, Tang CC, Chang YC, Huang SY, Chen CH, Wu SC, Hsieh SP, Hsieh CS, Wang KY, Lin SY, Lee HL, Lee CH, Kuo HC, Chen WF, Jean YH. Intra-articular injection of the selective cyclooxygenase-2 inhibitor meloxicam (Mobic) reduces experimental osteoarthritis and nociception in rats. Osteoarthritis Cartilage 2013; 21:1976-86. [PMID: 24084190 DOI: 10.1016/j.joca.2013.09.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 09/09/2013] [Accepted: 09/16/2013] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To study the effect of intra-articular injection of meloxicam (Mobic) on the development of osteoarthritis (OA) in rats and examine concomitant changes in nociceptive behavior and the expression of mitogen-activated protein kinases (MAPKs) in articular cartilage chondrocytes. METHODS OA was induced in Wistar rats by right anterior cruciate ligament transection (ACLT); the left knee was not treated. The OA + meloxicam (1.0 mg) group was injected intra-articularly in the ACLT knee with 1.0 mg of meloxicam once a week for 5 consecutive weeks starting 5 weeks after ACLT. The OA + meloxicam (0.25 mg) group was treated similarly with 0.25 mg meloxicam. The sham group underwent arthrotomy only and received vehicle of 0.1 mL sterile 0.9% saline injections, whereas the naive rats in meloxicam-only groups were treated similarly with 1.0- and 0.25-mg meloxicam. Nociception was measured as secondary mechanical allodynia and hind paw weight-bearing distribution at before (pre-) and 5, 10, 15, and 20 weeks post-ACLT. Histopathology of the cartilage and synovia was examined 20 weeks after ACLT. Immunohistochemical analysis was performed to examine the effect of meloxicam on MAPKs (p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK)) expression in the articular cartilage chondrocytes. RESULTS OA rats receiving intra-articular meloxicam treatment showed significantly less cartilage degeneration and synovitis than saline-treated controls. Nociception were improved in the OA + meloxicam groups compared with the OA group. Moreover, meloxicam attenuated p38 and JNK but enhanced ERK expression in OA-affected cartilage. CONCLUSIONS Intra-articular injection of meloxicam (1) attenuates the development of OA, (2) concomitantly reduces nociception, and (3) modulates chondrocyte metabolism, possibly through inhibition of cellular p38 and JNK, but enhances ERK expression.
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Affiliation(s)
- Z-H Wen
- Department of Marine Biotechnology & Resources, Asian Pacific Ocean Research Center, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Tsai PH, Lee HS, Siow TY, Chang YC, Chou MC, Lin MH, Lin CY, Chung HW, Huang GS. Sequential change in T2* values of cartilage, meniscus, and subchondral bone marrow in a rat model of knee osteoarthritis. PLoS One 2013; 8:e76658. [PMID: 24204653 PMCID: PMC3799892 DOI: 10.1371/journal.pone.0076658] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2013] [Accepted: 08/26/2013] [Indexed: 12/02/2022] Open
Abstract
Background There is an emerging interest in using magnetic resonance imaging (MRI) T2* measurement for the evaluation of degenerative cartilage in osteoarthritis (OA). However, relatively few studies have addressed OA-related changes in adjacent knee structures. This study used MRI T2* measurement to investigate sequential changes in knee cartilage, meniscus, and subchondral bone marrow in a rat OA model induced by anterior cruciate ligament transection (ACLX). Materials and Methods Eighteen male Sprague Dawley rats were randomly separated into three groups (n = 6 each group). Group 1 was the normal control group. Groups 2 and 3 received ACLX and sham-ACLX, respectively, of the right knee. T2* values were measured in the knee cartilage, the meniscus, and femoral subchondral bone marrow of all rats at 0, 4, 13, and 18 weeks after surgery. Results Cartilage T2* values were significantly higher at 4, 13, and 18 weeks postoperatively in rats of the ACLX group than in rats of the control and sham groups (p<0.001). In the ACLX group (compared to the sham and control groups), T2* values increased significantly first in the posterior horn of the medial meniscus at 4 weeks (p = 0.001), then in the anterior horn of the medial meniscus at 13 weeks (p<0.001), and began to increase significantly in the femoral subchondral bone marrow at 13 weeks (p = 0.043). Conclusion Quantitative MR T2* measurements of OA-related tissues are feasible. Sequential change in T2* over time in cartilage, meniscus, and subchondral bone marrow were documented. This information could be potentially useful for in vivo monitoring of disease progression.
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Affiliation(s)
- Ping-Huei Tsai
- Imaging Research Center, Taipei Medical University, Taipei, Taiwan
- Department of Medical Imaging, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan
| | - Herng-Sheng Lee
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tiing Yee Siow
- Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan
| | - Yue-Cune Chang
- Department of Mathematics, Tamkang University, Taipei, Taiwan
| | - Ming-Chung Chou
- Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Huang Lin
- Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan
| | - Chien-Yuan Lin
- Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan
| | - Hsiao-Wen Chung
- Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
| | - Guo-Shu Huang
- Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- * E-mail:
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Tsai WY, Wu JL, Liu CC, Cherng CH, Tsai RY, Jean YH, Wong CS. Early intraarticular injection of hyaluronic acid attenuates osteoarthritis progression in anterior cruciate ligament-transected rats. Connect Tissue Res 2012; 54:49-54. [PMID: 23020698 DOI: 10.3109/03008207.2012.734877] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
SUBJECT Hyaluronic acid (HA) is widely used to relieve the symptoms of osteoarthritis (OA). An association of reduction of glutamate content with the synovial fluid of OA rats was reported previously. DESIGN Anterior cruciate ligament transaction (ACLT) was performed on one knee in male Wistar rats, the other knee was assigned to sham control and HA or saline was injected intraarticularly into the ACLT knee from week 3 to week 7. Knee dialysate was collected for amino acid measurement at week 20. Morphology and histopathology of the femoral medial condyles and synovium were examined and evaluated using Mankin and synovitis scores. RESULTS HA injection provided better cartilage (3.38 ± 0.03 vs. 5.45 ± 0.0.02) and synovial condition (3 ± 0.02 vs. 6.03 ± 0.02) than saline controls. Moreover, HA injection reduced the concentration of glutamates in knee dialysates compared to saline controls (1.11 ± 0.14-folds and 2.21 ± 0.19-folds of the sham-operated knee, respectively). Cystine/glutamate antiporter system [Formula: see text] expression was significantly downregulated in the saline group, but not in the HA group (0.32 ± 0.08-folds and 0.71 ± 0.10-folds of the sham-operated knee, respectively). CONCLUSION Early intraarticular injection of HA attenuates the progression of cartilage destruction in the ACLT knee, and the downregulation of the cystine/glutamate antiporter system [Formula: see text] was accompanied by the progression of OA.
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Affiliation(s)
- Wei-Yuan Tsai
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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Li J, Gorski DJ, Anemaet W, Velasco J, Takeuchi J, Sandy JD, Plaas A. Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism. Arthritis Res Ther 2012; 14:R151. [PMID: 22721434 PMCID: PMC3446537 DOI: 10.1186/ar3887] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 05/22/2012] [Accepted: 06/21/2012] [Indexed: 12/12/2022] Open
Abstract
Introduction The mechanism by which intra-articular injection of hyaluronan (HA) ameliorates joint pathology is unknown. Animal studies have shown that HA can reduce synovial activation, periarticular fibrosis and cartilage erosion; however, its specific effects on the different cell types involved remain unclear. We have used the TTR (TGFbeta1 injection and Treadmill Running) model of murine osteoarthritis (OA), which exhibits many OA-like changes, including synovial activation, to examine in vivo tissue-specific effects of intra-articular HA. Methods The kinetics of clearance of fluorotagged HA from joints was examined with whole-body imaging. Naïve and treated knee joints were examined macroscopically for cartilage erosion, meniscal damage and fibrosis. Quantitative histopathology was done with Safranin O for cartilage and with Hematoxylin & Eosin for synovium. Gene expression in joint tissues for Acan, Col1a1, Col2a1, Col3a1, Col5a1, Col10a1, Adamts5 and Mmp13 was done by quantitative PCR. The abundance and distribution of aggrecan, collagen types I, II, III, V and X, ADAMTS5 and MMP13 were examined by immunohistochemistry. Results Injected HA showed a half-life of less than 2 h in the murine knee joint. At the tissue level, HA protected against neovascularization and fibrosis of the meniscus/synovium and maintained articular cartilage integrity in wild-type but not in Cd44 knockout mice. HA injection enhanced the expression of chondrogenic genes and proteins and blocked that of fibrogenic/degradative genes and proteins in cartilage/subchondral bone, whereas it blocked activation of both groups in meniscus/synovium. In all locations it reduced the expression/protein for Mmp13 and blocked Adamts5 expression but not its protein abundance in the synovial lining. Conclusions The injection of HA, 24 h after TGFbeta1 injection, inhibited the cascade of OA-like joint changes seen after treadmill use in the TTR model of OA. In terms of mechanism, tissue protection by HA injection was abrogated by Cd44 ablation, suggesting that interaction of the injected HA with CD44 is central to its protective effects on joint tissue remodeling and degeneration in OA progression.
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Affiliation(s)
- Jun Li
- Department of Internal Medicine (Rheumatology), Rush University Medical Center, 1611 West Harrison Street Suite 510, Chicago, IL 60612, USA
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McArthur BA, Dy CJ, Fabricant PD, Valle AGD. Long term safety, efficacy, and patient acceptability of hyaluronic acid injection in patients with painful osteoarthritis of the knee. Patient Prefer Adherence 2012; 6:905-10. [PMID: 23271899 PMCID: PMC3526887 DOI: 10.2147/ppa.s27783] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The increasing prevalence of painful knee osteoarthritis has created an additional demand for pharmacologic management to prevent or delay surgical management. Viscosupplementation, via intraarticular injection of hyaluronic acid (HA), aims to restore the favorable milieu present in the nonarthritic joint. The safety profile of intraarticular HA injections for painful knee osteoarthritis is well established, with the most common adverse effect being a self-limited reaction at the injection site. Although acceptance of the early literature has been limited by publication bias and poor study quality, more recent and rigorous meta-analysis suggests that intraarticular HA injection is superior to placebo injection for pain relief and matches, if not surpasses, the effect size of other nonoperative treatments, such as nonsteroidal anti-inflammatory medication. Intraarticular HA injection is effective in providing temporary pain relief in patients with painful knee osteoarthritis. Future investigations should focus on optimizing the composition and administration of HA agents to provide prolonged relief of painful osteoarthritis in the knee and other joints.
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Affiliation(s)
| | - Christopher J Dy
- Correspondence: Christopher J Dy, 535 E 70th Street, New York, NY, USA, Tel +1 212 606 1466, Fax +1 212 606 1477, Email
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Qi Y, Feng G, Yan W. Mesenchymal stem cell-based treatment for cartilage defects in osteoarthritis. Mol Biol Rep 2011; 39:5683-9. [DOI: 10.1007/s11033-011-1376-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Accepted: 12/13/2011] [Indexed: 12/20/2022]
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Lee JM, Im GI. SOX trio-co-transduced adipose stem cells in fibrin gel to enhance cartilage repair and delay the progression of osteoarthritis in the rat. Biomaterials 2011; 33:2016-24. [PMID: 22189147 DOI: 10.1016/j.biomaterials.2011.11.050] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2011] [Accepted: 11/20/2011] [Indexed: 12/15/2022]
Abstract
The aim of this study was to test the hypotheses that retroviral gene transfer of SOX trio enhances the in vitro chondrogenic differentiation of ASCs, and that SOX trio-co-transduced ASCs in fibrin gel promote the healing of osteochondral defects, and arrest the progression of surgically-induced osteoarthritis in a rat model. ASCs isolated from inguinal fat in rats were transduced with SOX trio genes using retrovirus, and further cultured in vitro in pellets for 21 days, then analyzed for gene and protein expression of SOX trio and chondrogenic markers. SOX trio-co-transduced ASCs in fibrin gel were implanted on the osteochondral defect created in the patellar groove of the distal femur, and also injected into the knee joints of rats with surgically-induced osteoarthritis. Rats were sacrificed after 8 weeks, and analyzed grossly and microscopically. After 21 days, ASCs transduced with SOX-5, -6, or -9 had hundreds-fold greater gene expression of each gene compared with the control with the SOX protein expression matching gene expression. SOX trio-co-transduction significantly increased GAG contents as well as type II collagen gene and protein expression. ASCs co-transduced with SOX trio significantly promoted the in vivo cartilage healing in osteochondral defect model, and prevented the progression of degenerative changes in surgically-induced osteoarthritis.
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Affiliation(s)
- Jong-Min Lee
- Department of Orthopaedics, Dongguk University Ilsan Hospital, 814 Siksa-Dong, Goyang 411-773, Republic of Korea
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Jazrawi LM, Rosen J. Intra-articular hyaluronic acid: potential treatment of younger patients with knee injury and/or post-traumatic arthritis. PHYSICIAN SPORTSMED 2011; 39:107-13. [PMID: 21673490 DOI: 10.3810/psm.2011.05.1900] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Anterior cruciate ligament (ACL) and meniscal injuries are common in both athletes and the general population. Such injuries may lead to early-onset post-traumatic osteoarthritis (OA) in 50% to 60% of patients, regardless of whether patients had reconstruction performed. In younger patients, intra-articular (IA) injection of hyaluronic acid (HA) may be useful for improving short-term outcomes and possibly slowing or arresting the progression of OA. Hyaluronic acid has anti-inflammatory, anabolic, and chondroprotective effects, which have been demonstrated in in vitro and animal models of meniscal and ACL injury. Results from several clinical trials and patient series have demonstrated the benefit of IA HA injection in younger patients with acute knee damage, including symptomatic meniscal tears and isolated ACL injury with chondral injury, although evidence for this is less extensive than the large database supporting the use of IA HA injection in older patients with knee OA. Administration of HA has been shown to improve outcomes in patients undergoing knee arthroscopy, and IA HA also has direct antinociceptive effects that may contribute to its benefit in patients with patellofemoral pain. However, the use of IA HA in patients with ACL injury or early OA has been evaluated in only a few studies. Thus, there is a need for larger-scale randomized controlled trials with longer durations of follow-up to provide more definitive evaluation of the efficacy and safety of IA HA in these patients. Such studies provide an opportunity to further elucidate the benefits of IA HA in younger patients with knee damage and may result in appropriate expansion of use in this large population, which has a substantial need for new treatment alternatives.
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Affiliation(s)
- Laith M Jazrawi
- New York University Hospital for Joint Diseases, New York, NY, USA.
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Toghraie FS, Chenari N, Gholipour MA, Faghih Z, Torabinejad S, Dehghani S, Ghaderi A. Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in Rabbit. Knee 2011; 18:71-75. [PMID: 20591677 DOI: 10.1016/j.knee.2010.03.001] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2010] [Revised: 02/20/2010] [Accepted: 03/07/2010] [Indexed: 02/02/2023]
Abstract
Osteoarthritis (OA) is a progressively debilitating disease that affects mostly cartilage, with associated changes in the bone. Increasing incidence of OA and the aging population coupled with insufficient therapeutic choices has led to focus on the potential of stem cells as a novel strategy for cartilage repair. In this study, we used scaffold free mesenchymal stem cells obtained from infrapatellar fat pad in an experimental animal model of OA by direct intraarticular injection. Mesenchymal stem cells isolated from a 2.8kg White New Zealand rabbit. The cells were expanded and grown in vitro. OA was induced by unilaterally anterior cruciate ligament transection of knee joints. Twelve weeks after operation, a single dose of 1 million cells suspended in 1ml of medium was delivered to the injured knee by direct intraarticular injection. Control group received 1ml of medium without cells. The knees were examined after sixteen and twenty weeks from the surgery. Repairing was investigated radiologically, grossly and histologically using haematoxylin and eosin, Safranin-O and toluidine blue staining. Radiological assessment confirmed development of OA changes after 12 weeks. Rabbits receiving mesenchymal stem cells showed lower degree of cartilage degeneration, osteophyte formation, and Subchondral sclerosis than control group at 20 week after surgery. The quality of cartilage was significantly better in cell-treated group compared with control group after 20 weeks. In conclusion, infrapatellar fat pad derived mesenchymal stem cells could be the promising cell sources for the treatment of OA.
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Affiliation(s)
- F S Toghraie
- Faculty of Vet Medicine, Shiraz University, Iran
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Shen PC, Shiau AL, Jou IM, Lee CH, Tai MH, Juan HY, Lin PR, Liu GS, Wu CL, Hsieh JL. Inhibition of cartilage damage by pro-opiomelanocortin prohormone overexpression in a rat model of osteoarthritis. Exp Biol Med (Maywood) 2011; 236:334-340. [PMID: 21378032 DOI: 10.1258/ebm.2010.010319] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Pro-opiomelanocortin (POMC) is a precursor of various neuropeptides. POMC-derived neuropeptides are potent inflammation inhibitors and immunosuppressants. Evidence that osteoarthritis (OA) is an inflammatory disease is accumulating. We assessed whether intra-articular gene delivery of POMC ameliorates experimentally induced OA in a rat model. OA was induced in Wistar rats by anterior cruciate ligament-transection (ACLT) in the knee of one hind limb. Adenoviral vector encoding human POMC (AdPOMC) was injected intra-articularly into the knee joints after ACLT. The transgene expression and the inflammatory responses were evaluated using immunoblotting, immunohistochemistry and enzyme-linked immunosorbent assay. The treated joints were assessed histologically for manifestations of the disease. Human POMC was expressed in the chondrocytes and synovial membrane after the intra-articular injection. POMC gene transfer reduced nuclear factor-κB activity and the levels of interleukin-1β in HTB-94 chondrosarcoma cells and Raw 264.7 macrophages; it also reduced microvessel density in the synovium. Histological examination showed that symptoms of OA in AdPOMC-treated rats were less severe than in rats treated with either empty adenoviral vector (AdNull) or normal saline. Intra-articular injection of adenoviral vectors expressing POMC significantly suppressed the progression and severity of OA, and reduced inflammatory responses and angiogenesis. POMC gene delivery may offer novel therapeutic approach for treating OA.
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Affiliation(s)
- Po-Chuan Shen
- Department of Orthopedic Surgery, Tainan Hospital, Department of Health, Executive Yuan, Taiwan
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Miller KE, Hoffman EM, Sutharshan M, Schechter R. Glutamate pharmacology and metabolism in peripheral primary afferents: physiological and pathophysiological mechanisms. Pharmacol Ther 2011; 130:283-309. [PMID: 21276816 DOI: 10.1016/j.pharmthera.2011.01.005] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2011] [Accepted: 01/05/2011] [Indexed: 11/25/2022]
Abstract
In addition to using glutamate as a neurotransmitter at central synapses, many primary sensory neurons release glutamate from peripheral terminals. Primary sensory neurons with cell bodies in dorsal root or trigeminal ganglia produce glutaminase, the synthetic enzyme for glutamate, and transport the enzyme in mitochondria to peripheral terminals. Vesicular glutamate transporters fill neurotransmitter vesicles with glutamate and they are shipped to peripheral terminals. Intense noxious stimuli or tissue damage causes glutamate to be released from peripheral afferent nerve terminals and augmented release occurs during acute and chronic inflammation. The site of action for glutamate can be at the autologous or nearby nerve terminals. Peripheral nerve terminals contain both ionotropic and metabotropic excitatory amino acid receptors (EAARs) and activation of these receptors can lower the activation threshold and increase the excitability of primary afferents. Antagonism of EAARs can reduce excitability of activated afferents and produce antinociception in many animal models of acute and chronic pain. Glutamate injected into human skin and muscle causes acute pain. Trauma in humans, such as arthritis, myalgia, and tendonitis, elevates glutamate levels in affected tissues. There is evidence that EAAR antagonism at peripheral sites can provide relief in some chronic pain sufferers.
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Affiliation(s)
- Kenneth E Miller
- Department of Anatomy and Cell Biology, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, United States.
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Edouard P, Rannou F, Coudeyre E. Visco-induction et chondropathie post-traumatique du genou: existe-t-il des preuves fondamentales ? ACTA ACUST UNITED AC 2011. [DOI: 10.1007/s11659-010-0254-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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Oryan A, Moshiri A, Meimandiparizi AH. Effects of sodium-hyaluronate and glucosamine-chondroitin sulfate on remodeling stage of tenotomized superficial digital flexor tendon in rabbits: a clinical, histopathological, ultrastructural, and biomechanical study. Connect Tissue Res 2010; 52:329-39. [PMID: 21117902 DOI: 10.3109/03008207.2010.531332] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This study was designed to evaluate the effects of sodium-hyaluronate (NaH) combined with glucosamine HCl-chondroitin sulfate (GlcN-CS) on the post-surgical repair of tendon rupture on day 84 post injury. Twenty white New Zealand female rabbits were divided randomly into two equal groups of injured treated and injured untreated. After tenotomy and surgical repair, using the modified Kessler technique and running pattern, the injured legs were casted for 14 days. NaH was injected subcutaneously over the lesion on days 3, 7, and 10 and was followed by daily oral administration of GlcN-CS on days 3 to 23 post injury. The control animals received normal saline injection and oral placebo similarly. The weight of the animals, tendon diameter, clinical manifestations, and radiographic and ultrasonographic evaluations were conducted for 12 weeks. The rabbits were euthanized 84 days post injury and the tendons were evaluated at macroscopic, histopathologic, and ultrastructural level and were assessed for biomechanical and percentage dry-weight parameters. Treatment significantly reduced the tendon diameter and ultimate and yield strain, and increased the echogenicity, dry-weight content, ultimate and yield strength, and stress and stiffness of the injured tendons compared to those of the untreated ones. Treatment also significantly enhanced the maturation rate of the tenoblasts, fibrillogenesis, the diameters of the collagen fibrils, and fibrillar density. These findings suggest that a combined treatment of NaH and GlcN-CS could be effective in restoring the morphological and biomechanical properties of injured superficial digital flexor tendon of rabbits and might be helpful for future clinical trial studies in tendon ruptures.
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Affiliation(s)
- Ahmad Oryan
- Department of Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran.
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Hsieh JL, Shen PC, Shiau AL, Jou IM, Lee CH, Wang CR, Teo ML, Wu CL. Intraarticular gene transfer of thrombospondin-1 suppresses the disease progression of experimental osteoarthritis. J Orthop Res 2010; 28:1300-6. [PMID: 20309955 DOI: 10.1002/jor.21134] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In osteoarthritis, angiogenesis, which occurs in the osteochondral junction and synovium, may accelerate inflammation and contribute to the severity of the disease. We used anterior cruciate ligament-transection (ACLT) to investigate the therapeutic effect of an angiogenesis inhibitor, thrombospondin-1 (TSP-1), in a rat model of osteoarthritis. Osteoarthritis was induced in Wistar rats in the knee of one hind leg. After ACLT, AdTSP-1 (adenoviral vector encoding mouse TSP-1) was intraarticularly injected into the knee joints. Transgene expression, angiogenesis, and inflammatory responses in the knee joints were examined. They were also assessed morphologically, radiographically, and histologically for manifestations of disease. The levels of TSP-1 peaked on day 3 and were substantially maintained for at least 9 days after AdTSP-1 infection. Adenovirus-mediated gene expression was detected in the synovial membrane and chondrocytes. TSP-1 gene transfer induced transforming growth factor-β (TGF-β) production, but it reduced microvessel density, macrophage infiltration, and interleukin-1β (IL-1β) levels. Gross morphological and histopathological examinations revealed that rats treated with AdTSP-1 had less severe osteoarthritis than controls. In vivo adenovirus-mediated TSP-1 gene transfer significantly reduced microvessel density, inflammation, and suppressed the progression of osteoarthritis. This study provides potential applications of TSP-1 gene delivery for treating osteoarthritis.
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Affiliation(s)
- Jeng-Long Hsieh
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan Hsien, Taiwan
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Naito K, Watari T, Muta T, Furuhata A, Iwase H, Igarashi M, Kurosawa H, Nagaoka I, Kaneko K. Low-intensity pulsed ultrasound (LIPUS) increases the articular cartilage type II collagen in a rat osteoarthritis model. J Orthop Res 2010; 28:361-9. [PMID: 19810106 DOI: 10.1002/jor.20995] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
In this study, the effect of low-intensity pulsed ultrasound (LIPUS) on cartilage was evaluated in a rat osteoarthritis (OA) model using serum biomarkers such as CTX-II (type II collagen degradation) and CPII (type II collagen synthesis) as well as histological criteria (Mankin score and immunohistochemical type II collagen staining). OA was surgically induced in the knee joint of rats by anterior cruciate/medial collateral ligament transection and medial meniscus resection (ACLT + MMx). Animals were divided into three groups: sham-operated group (Sham), ACLT + MMx group without LIPUS (-LIPUS), and ACLT + MMx group with LIPUS (+LIPUS; 30 mW/cm(2), 20 min/day for 28 days). CTX-II levels were elevated in both -LIPUS and +LIPUS groups compared to that in the Sham group after the operation, but there was no significant difference between +LIPUS and -LIPUS groups, suggesting that LIPUS does not affect the degradation of type II collagen in this model. In contrast, CPII was significantly increased in +LIPUS group compared to -LIPUS and Sham. Moreover, histological damage on the cartilage (Mankin score) was ameliorated by LIPUS, and type II collagen was immunohistochemically increased by LIPUS in the cartilage of an OA model. Of interest, mRNA expression of type II collagen was enhanced by LIPUS in chondrocytes. Together these observations suggest that LIPUS is likely to increase the type II collagen synthesis in articular cartilage, possibly via the activation of chondrocytes and induction of type II collagen mRNA expression, thereby exhibiting chondroprotective action in a rat OA model.
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Affiliation(s)
- Kiyohito Naito
- Department of Orthopaedic Surgery, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295, Japan.
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Naito K, Watari T, Furuhata A, Yomogida S, Sakamoto K, Kurosawa H, Kaneko K, Nagaoka I. Evaluation of the effect of glucosamine on an experimental rat osteoarthritis model. Life Sci 2010; 86:538-43. [PMID: 20188111 DOI: 10.1016/j.lfs.2010.02.015] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2009] [Revised: 02/01/2010] [Accepted: 02/07/2010] [Indexed: 11/19/2022]
Abstract
AIMS To investigate the in vivo effect of glucosamine on articular cartilage in osteoarthritis (OA), we evaluated serum biomarkers such as CTX-II (type II collagen degradation) and CPII (type II collagen synthesis) as well as histopathological changes (Mankin score, toluidine blue staining of proteoglycans in an experimental OA model using rats. MAIN METHODS OA was surgically induced in the knee joint by anterior cruciate ligament transection (ACLT) in rats. Animals were divided into three groups: sham-operated group (Sham), ACLT group without GlcN administration (-GlcN) and ACLT group with oral administration of glucosamine hydrochloride (+GlcN; 1000mg/kg/day for 56days). KEY FINDINGS ACLT induced macroscopic erosive changes on the surfaces of articular cartilage and histological damages such as increase of Mankin score. Of note, glucosamine administration substantially suppressed the macroscopic changes, although the effect on Mankin score was not significant. In addition, serum CTX-II levels were elevated in -GlcN group compared to that in Sham group after the operation. Of importance, the increase of CTX-II was significantly suppressed by GlcN administration. Moreover, serum CP-II levels were substantially increased in +GlcN group compared to those in Sham and -GlcN groups after the operation. SIGNIFICANCE GlcN has a potential to exert a chondroprotective action on OA by inhibiting type II collagen degradation and enhancing type II collagen synthesis in the articular cartilage.
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Affiliation(s)
- Kiyohito Naito
- Department of Orthopaedic Surgery, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni, Shizuoka 410-2295, Japan
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Huang GS, Lee HS, Chou MC, Shih YYI, Tsai PH, Lin MH, Lin CY, Lee CH, Chung HW. Quantitative MR T2 measurement of articular cartilage to assess the treatment effect of intra-articular hyaluronic acid injection on experimental osteoarthritis induced by ACLX. Osteoarthritis Cartilage 2010; 18:54-60. [PMID: 19761884 DOI: 10.1016/j.joca.2009.08.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 07/27/2009] [Accepted: 08/20/2009] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate whether the effect of treatment with hyaluronic acid (HA) on cartilage in osteoarthritis (OA) can be determined by measuring the magnetic resonance (MR) T2 value of cartilage in an anterior cruciate ligament transection (ACLX) animal model. METHOD Eighteen male Sprague Dawley rats were separated randomly into three groups (n=6 for each group). Group 1 was given ACLX and intra-articular (IA) normal saline (NS) injection (ACLX+NS), group 2 was given ACLX and IA HA injection (ACLX+HA), and group 3 was the sham control. The ACLX+NS and ACLX+HA groups received ACLX on the right knee at 8 weeks of age and were then treated with IA NS or HA injection once a week, respectively, for 4 weeks starting at 13 weeks of age. In the sham-control group, the right knee joint was opened surgically but ACLX was not performed at 8 weeks of age. MR T2 measurements were obtained on all rats at 8, 12, and 21 weeks of age, and histological Mankin scoring was performed at 21 weeks of age. RESULTS Five weeks after the 4-week treatment, the MR T2 value of the ACLX right knee cartilage was significantly lower in ACLX+HA (29.58+/-1.12ms) than in ACLX+NS (32.04+/-1.39ms) (P<0.05). Five weeks after the 4-week treatment, the Mankin score of the ACLX right knee was significantly lower in ACLX+HA (3.3+/-0.81) than in ACLX+NS (7.3+/-1.03) (P<0.001). The T2 value was significantly and positively correlated with the Mankin score in the ACLX+NS (rho=0.77, P<0.05) and ACLX+HA (rho=0.69, P<0.05) groups. CONCLUSION This study demonstrates the feasibility of quantitative MR T2 measurement in the early assessment of HA treatment efficiency in a cartilage degeneration model.
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Affiliation(s)
- G-S Huang
- Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
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Lee CH, Wen ZH, Chang YC, Huang SY, Tang CC, Chen WF, Hsieh SP, Hsieh CS, Jean YH. Intra-articular magnesium sulfate (MgSO4) reduces experimental osteoarthritis and nociception: association with attenuation of N-methyl-D-aspartate (NMDA) receptor subunit 1 phosphorylation and apoptosis in rat chondrocytes. Osteoarthritis Cartilage 2009; 17:1485-93. [PMID: 19490963 DOI: 10.1016/j.joca.2009.05.006] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2009] [Revised: 04/03/2009] [Accepted: 05/04/2009] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To study the effects of intra-articular injection of magnesium sulfate (MgSO(4)) on the development of osteoarthritis (OA) and to examine concomitant changes in the nociceptive behavior of rats. METHODS OA was induced in Wistar rats with intra-articular injection of collagenase (500 U) in the right knee; the left knee was left untreated. In the OA+MgSO(4) group (n=7), the treated knee was injected with 500-microg (0.1-ml) MgSO(4) twice a week for 5 consecutive weeks starting at 1 week after collagenase injection; in the OA group (n=7), the same knee was injected with the same amount of physiological normal saline. In the MgSO(4) group (n=6), naïve rats received only MgSO(4) injections; in the control group (n=6), naïve rats received only physiological normal saline injections. Nociceptive behavior (mechanical allodynia and thermal hyperalgesia) on OA development was measured before and at 1, 2, 4, 6, and 8 weeks after collagenase injection, following which the animals were sacrificed. Gross morphology and histopathology were examined in the femoral condyles, tibial plateau, and synovia. Immunohistochemical analysis was performed to examine the effect of MgSO(4) on N-methyl-D-aspartate (NMDA) receptor subunit 1 phosphorylation (p-NR1) and apoptosis in the articular cartilage chondrocytes. RESULTS OA rats receiving intra-articular MgSO(4) injections showed a significantly lower degree of cartilage degeneration than the rats receiving saline injections. MgSO(4) treatment also suppressed synovitis. Mechanical allodynia and thermal hyperalgesia showed significant improvement in the OA+MgSO(4) group as compared to the OA group. Moreover, MgSO(4) attenuated p-NR1 and chondrocyte apoptosis in OA-affected cartilage. CONCLUSIONS Our results indicate that local intra-articular administration of MgSO(4) following collagenase injection in an experimental rat OA model (1) modulates chondrocyte metabolism through inhibition of cell NMDA receptor phosphorylation and apoptosis, (2) attenuates the development of OA, and (3) concomitantly reduces nociception.
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Affiliation(s)
- C H Lee
- Department of Orthopedics and Traumatology, Taipei Medical University Hospital, Taipei, Taiwan
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Yucel I, Karaca E, Ozturan K, Yildirim U, Duman S, Degirmenci E. Biomechanical and histological effects of intra-articular hyaluronic acid on anterior cruciate ligament in rats. Clin Biomech (Bristol, Avon) 2009; 24:571-6. [PMID: 19464776 DOI: 10.1016/j.clinbiomech.2009.04.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Revised: 04/25/2009] [Accepted: 04/27/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND The histologic and biomechanical effects of intra-articular hyaluronic acid on the anterior cruciate ligaments of rats were investigated. METHODS Thirty rats were divided into three groups, i.e., the hyaluronic acid group, saline group, and control group. The hyaluronic acid and saline groups received a total of four intra-articular injections, whereas no injection was administered to the control group. The hyaluronic acid group was injected with 50 microg (0.05 cc) hyaluronic acid, and the saline group was injected with 50 microl (0.05 cc) of 0.9% sodium chloride solution. All of the rats were sacrificed on day 29 and the femur-anterior cruciate ligament-tibia complexes from the right knees were prepared, tested mechanically, and evaluated histologically. FINDINGS The mode of failure involved the midsubstance of the anterior cruciate ligament in all the specimens. There were no statistically significant differences in the stiffness and ultimate load to failure values between the three groups (P>0.05). The energy to failure values were evaluated and there was no statistically significant difference between the groups (P=0.064, chi-square=3.43). In the histologic analyses, there was a significant difference in the hyalinization values between the hyaluronic acid and saline groups (P=0.029) and between the hyaluronic acid group and control groups (P=0.029). INTERPRETATION The present study shows that intra-articularly delivered hyaluronic acid has no statistically significant effect on the tensile strength of the rat anterior cruciate ligament. Although hyalinization was increased, no difference was found on the other markers for degenerative changes. We conclude that intra-articular hyaluronic acid injections can be performed safely, although the use of a precise injection technique is recommended.
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Affiliation(s)
- Istemi Yucel
- Department of Orthopaedics and Traumatology, Faculty of Medicine, University of Duzce, Duzce, Turkey.
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Killian ML, Isaac DI, Haut RC, Déjardin LM, Leetun D, Donahue TLH. Traumatic anterior cruciate ligament tear and its implications on meniscal degradation: a preliminary novel lapine osteoarthritis model. J Surg Res 2009; 164:234-41. [PMID: 19577765 DOI: 10.1016/j.jss.2009.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2009] [Revised: 02/19/2009] [Accepted: 03/03/2009] [Indexed: 01/31/2023]
Abstract
BACKGROUND Injury patterns of the meniscus following impact trauma resulting in anterior cruciate ligament (ACL) rupture are not well understood. This study explored the spatial and temporal distribution of meniscal tears in a novel in vivo lapine model. METHODS Skeletally mature Flemish Giant rabbits were subjected to either tibiofemoral impaction resulting in ACL rupture or surgical ACL transection. Meniscal damage was assessed acutely and after 12 wk for traumatically torn, and after 12 wk in ACL transected animals. Morphological grading was assessed using previously established criteria, and descriptions of meniscal damage were diagnosed by a Board certified orthopedist. Histological assessment was also made on 12 wk traumatically torn and ACL transected animals using Fast-Green/Safranin-O staining. RESULTS Traumatic ACL rupture resulted in acute tears predominately in the lateral menisci. Animals subjected to both surgical transection and traumatic ACL rupture experienced degradation of the lateral and medial menisci 12 wk after injury. However, traumatic ACL rupture resulted in acute lateral damage and chronic degradation of the menisci, as well as more severe degradation of the menisci 12 wk after injury. CONCLUSIONS This study showed that unconstrained high-intensity impacts on the tibiofemoral joint lead to meniscal damage in conjunction with ACL ruptures. Both acute and chronic changes to the menisci following traumatic impaction were observed. This research has implications for the future use of lapine models for osteoarthritis, as it incorporates traumatic loading as a more realistic mode contributing to the progression of osteoarthritis (OA) compared to surgically transected models.
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Affiliation(s)
- Megan L Killian
- Soft Tissue Mechanics Laboratory, Mechanical Engineering-Engineering Mechanics, Michigan Technological University, Houghton, Michigan 49931, USA
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Correlation between the MR T2 value at 4.7 T and relative water content in articular cartilage in experimental osteoarthritis induced by ACL transection. Osteoarthritis Cartilage 2009; 17:441-7. [PMID: 18990590 DOI: 10.1016/j.joca.2008.09.009] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2008] [Accepted: 09/07/2008] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Both animal and human studies using magnetic resonance imaging (MRI) show that cartilage degeneration increases the T2 value. However, it is unclear whether the T2 value correlates linearly with water content in cartilage with osteoarthritis. The purpose of this study was to investigate the relationship between the T2 value and water content using an animal model of cartilage injury measured at 4.7 T. DESIGN Thirty Sprague Dawley rats were randomly separated into three groups (n=10 for each group). Group 1 rats were not operated on (control). Group 2 rats received a sham operation, and group 3 rats received an anterior cruciate ligament (ACL) transection. Six rats of each group were randomly assigned to T2 measurement and later subjected to ex vivo analysis of the relative water content of the knee cartilage. The other four rats in each group were killed, and the severity of cartilage degeneration was examined histologically. The knees of the six rats in the ACL transection group were imaged sequentially 4 and 13 weeks after ACL transection, and the relative water content was measured at 13 weeks. RESULTS The cartilage T2 value was significantly higher 4 and 13 weeks after ACL transection in the operated knees than in the knees of the control and sham groups. The cartilage T2 value was significantly higher at 13 weeks than at 4 weeks in the operated knees. The T2 value was strongly positively correlated with the relative water content (R=0.885, P<0.0001). CONCLUSION The trend of changes in the T2 values is consistent with an increase in the relative water content in our cartilage degeneration model. This model has potential use for the clinical evaluation of osteoarthritis.
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Hsieh JL, Shen PC, Shiau AL, Jou IM, Lee CH, Teo ML, Wang CR, Chao J, Chao L, Wu CL. Adenovirus-Mediated Kallistatin Gene Transfer Ameliorates Disease Progression in a Rat Model of Osteoarthritis Induced by Anterior Cruciate Ligament Transection. Hum Gene Ther 2009; 20:147-58. [DOI: 10.1089/hum.2008.096] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Jeng-Long Hsieh
- Department of Nursing, Chung Hwa University of Medical Technology, Tainan Hsien 717, Taiwan
| | - Po-Chuan Shen
- Department of Orthopedic Surgery, Tainan Hospital, Department of Health, Executive Yuan, Tainan 70034, Taiwan
| | - Ai-Li Shiau
- Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan
| | - I-Ming Jou
- Department of Orthopedics, National Cheng Kung University Medical College, Tainan 70101, Taiwan
| | - Che-Hsin Lee
- Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan
| | - Min-Li Teo
- Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan
| | - Chrong-Reen Wang
- Section of Rheumatology and Immunology, Department of Internal Medicine, National Cheng Kung University Medical College, Tainan 70101, Taiwan
| | - Julie Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
| | - Lee Chao
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425
| | - Chao-Liang Wu
- Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan 70101, Taiwan
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Jean YH, Wen ZH, Chang YC, Hsieh SP, Tang CC, Wang YH, Wong CS. Intra-articular injection of the cyclooxygenase-2 inhibitor parecoxib attenuates osteoarthritis progression in anterior cruciate ligament-transected knee in rats: role of excitatory amino acids. Osteoarthritis Cartilage 2007; 15:638-45. [PMID: 17198754 DOI: 10.1016/j.joca.2006.11.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2006] [Accepted: 11/21/2006] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Our present study examined the effect of intra-articular cyclooxygenase-2 (COX-2) inhibitor parecoxib on osteoarthritis (OA) progression and the concomitant changes in excitatory amino acids' (EAAs) levels of the anterior cruciate ligament-transected (ACLT) knee joint dialysates. METHODS OA was induced in Wistar rats by anterior cruciate ligament transection of the knee of one hindlimb, the other was left unoperated and untreated. Rats were placed into four groups: Group ACLT/P received intra-articular parecoxib injection (100 microg) in the ACLT knee once a week for 5 consecutive weeks starting at 8 weeks after surgery. Group ACLT/S received the same procedure as group ACLT/P with saline injection instead. Naïve (Naïve/P) rats received only intra-articular parecoxib injection in one knee once a week for 5 consecutive weeks without surgery. The sham-operated rats underwent arthrotomy only without treatment. Twenty weeks after surgery, knee joint dialysates were collected and EAAs' concentration was assayed by high-performance liquid chromatography, and gross morphology and histopathology (Mankin and synovitis grading) were examined on the medial femoral condyles and synovia. RESULTS Parecoxib alone had no effect on cartilage and synovium of normal knees in Naïve/P rats. In ACLT/P rats, parecoxib treatment showed a significant inhibition of cartilage degeneration of the medial femoral condyle at both the macroscopic level (1.15+/-0.17 vs 2.55+/-0.12, P<0.05) and the Mankin scores (3.03+/-0.28 vs 8.82+/-0.43, P<0.05). Intra-articular parecoxib injection also suppressed the synovial inflammation of ACLT joint compared to the ACLT/S group (3.92+/-0.41 vs 9.25+/-0.32, P<0.05). Moreover, glutamate and aspartate levels were also significantly reduced in the ACLT/P group compared to the ACLT/S group by parecoxib treatment (91.2+/-9.4% vs 189.5+/-17.0%, P<0.05 and 98.2+/-11.6% vs 175.3+/-12.4%, P<0.05, respectively). CONCLUSION This study shows that intra-articular injection of COX-2 inhibitor parecoxib inhibits the ACLT-induced OA progression; it was accompanied by a reduction of glutamate and aspartate concentration in the ACLT joint dialysates. From our present results, we suggested that intra-articular parecoxib injection, in addition to the anti-inflammatory effect, inhibiting the EAAs' release, may also play a role in inhibiting the traumatic knee injury induced OA progression.
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Affiliation(s)
- Y-H Jean
- Section of Orthopedic Surgery, Pingtung Christian Hospital, #60, Da-Lan Road, Pingtung 900, Taiwan
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Park YS, Lim SW, Lee IH, Lee TJ, Kim JS, Han JS. Intra-articular injection of a nutritive mixture solution protects articular cartilage from osteoarthritic progression induced by anterior cruciate ligament transection in mature rabbits: a randomized controlled trial. Arthritis Res Ther 2007; 9:R8. [PMID: 17257416 PMCID: PMC1860066 DOI: 10.1186/ar2114] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2006] [Revised: 12/15/2006] [Accepted: 01/26/2007] [Indexed: 11/21/2022] Open
Abstract
Osteoarthritis (OA) is a degenerative disease that disrupts the collagenous matrix of articular cartilage and is difficult to cure because articular cartilage is a nonvascular tissue. Treatment of OA has targeted macromolecular substitutes for cartilage components, such as hyaluronic acid or genetically engineered materials. However, the goal of the present study was to examine whether intra-articular injection of the elementary nutrients restores the matrix of arthritic knee joints in mature animals. A nutritive mixture solution (NMS) was composed of elementary nutrients such as glucose or dextrose, amino acids and ascorbic acid. It was administered five times (at weeks 6, 8, 10, 13 and 16) into the unilateral anterior cruciate ligament transected knee joints of mature New Zealand White rabbits, and the effect of NMS injection was compared with that of normal saline. OA progression was histopathologically evaluated by haematoxylin and eosin staining, by the Mankin grading method and by scanning electron microscopy at week 19. NMS injection decreased progressive erosion of articular cartilage overall compared with injection of normal saline (P < 0.01), and nms joints exhibited no differences relative to normal cartilage that had not undergone transection of the anterior cruciate ligament, as assessed using the mankin grading method. Haematoxylin and eosin staining and scanning electron microscopy findings also indicated that nms injection, in constrast to normal saline injection, restored the cartilage matrix, which is known to be composed of a collagen and proteoglycan network. thus, nms injection is a potent treatment that significantly retards oa progression, which in turn prevents progressive destruction of joints and functional loss in mature animals.
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Affiliation(s)
- Yoo-Sin Park
- Institute of Biomedical Science, College of Medicine 1F, Hanyang University, Haengdang-dong 17, Seongdong-gu, Seoul, 133-791, South Korea
| | - Si-Woong Lim
- Department of Physical Medicine and Rehabilitation, School of Medicine, Inje University, Gaekeum-dong 633-165, Pusanjin-gu, Pusan, 614-735, South Korea
- Chamsarang PM&R Clinic, Chonho-dong 455, Gangdong-gu, Seoul, 134-020, South Korea
| | - Il-Hoon Lee
- Department of Physical Medicine and Rehabilitation, School of Medicine, Inje University, Gaekeum-dong 633-165, Pusanjin-gu, Pusan, 614-735, South Korea
- Kwangmyung PM&R Clinic, Kwangmyung-dong 340-5, Kwangmyung, Gyunggi-do, 423-016, South Korea
| | - Tae-Jin Lee
- Department of Pathology, School of Medicine, Chungang University, Heukseok-dong, Dongjak-gu, Seoul, 155-756, South Korea
| | - Jong-Sung Kim
- Laboratory Animal Research Center, Samsung Biomedical Research Institute, Samsung Medical Center, Ilwon-dong 50, Gangnam-gu, Seoul, 135-710, South Korea
| | - Jin Soo Han
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Hwayang-dong 1, Gwangjin-gu, Seoul, 143-701, South Korea
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