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Xiao KZ, Liao G, Huang GY, Huang YL, Gu RH. Efficacy of serum-free cultured human umbilical cord mesenchymal stem cells in the treatment of knee osteoarthritis in mice. World J Stem Cells 2024; 16:944-955. [DOI: 10.4252/wjsc.v16.i11.944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/03/2024] [Accepted: 10/18/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND We investigated the efficacy of intra-articular injection of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of osteoarthritis (OA) progression in the knee joint. Although many experimental studies of hUC-MSCs have been published, these studies have mainly used fetal bovine serum-containing cultures of hUC-MSCs; serum-free cultures generally avoid the shortcomings of serum-containing cultures and are not subject to ethical limitations, have a wide range of prospects for clinical application, and provide a basis or animal experimentation for clinical experiments.
AIM To study the therapeutic effects of serum-free hUC-MSCs (N-hUCMSCs) in a mouse model of knee OA.
METHODS Fifty-five male C57BL/6 mice were randomly divided into six groups: The blank control group, model control group, serum-containing hUC-MSCs (S-hUCMSC) group, N-hUCMSC group and hyaluronic acid (HA) group. After 9 weeks of modeling, the serum levels of interleukin (IL)-1β and IL-1 were determined. Hematoxylin-eosin staining was used to observe the cartilage tissue, and the Mankin score was determined. Immunohistochemistry and western blotting were used to determine the expression of collagen type II, matrix metalloproteinase (MMP)-1 and MMP-13.
RESULTS The Mankin score and serum IL-1 and IL-1β and cartilage tissue MMP-1 and MMP-13 expression were significantly greater in the experimental group than in the blank control group (P < 0.05). Collagen II expression in the experimental group was significantly lower than that in the blank control group (P < 0.05). The Mankin score and serum IL-1 and IL-1β and cartilage tissue MMP-1 and MMP-13 levels the experimental group were lower than those in the model control group (P < 0.05). Collagen II expression in the experimental group was significantly greater than that in the model control group (P < 0.05).
CONCLUSION N-hUCMSC treatment significantly alleviate the pathological damage caused by OA. The treatment effects of the S- hUCMSC group and HA group were similar.
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Affiliation(s)
- Kai-Zhen Xiao
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Graduate School of Guangxi Medical University, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Gui Liao
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Guang-Yu Huang
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Graduate School of Guangxi Medical University, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Yun-Long Huang
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Graduate School of Guangxi Medical University, Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
| | - Rong-He Gu
- Department of Orthopedic Surgery, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
- Department of Guangxi Key Laboratory of Intelligent Medicine, The Fifth Affiliated Hospital of Guangxi Medical University, Nanning 530022, Guangxi Zhuang Autonomous Region, China
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Chondrocyte Hypertrophy in Osteoarthritis: Mechanistic Studies and Models for the Identification of New Therapeutic Strategies. Cells 2022; 11:cells11244034. [PMID: 36552796 PMCID: PMC9777397 DOI: 10.3390/cells11244034] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/08/2022] [Indexed: 12/16/2022] Open
Abstract
Articular cartilage shows limited self-healing ability owing to its low cellularity and avascularity. Untreated cartilage defects display an increased propensity to degenerate, leading to osteoarthritis (OA). During OA progression, articular chondrocytes are subjected to significant alterations in gene expression and phenotype, including a shift towards a hypertrophic-like state (with the expression of collagen type X, matrix metalloproteinases-13, and alkaline phosphatase) analogous to what eventuates during endochondral ossification. Present OA management strategies focus, however, exclusively on cartilage inflammation and degradation. A better understanding of the hypertrophic chondrocyte phenotype in OA might give new insights into its pathogenesis, suggesting potential disease-modifying therapeutic approaches. Recent developments in the field of cellular/molecular biology and tissue engineering proceeded in the direction of contrasting the onset of this hypertrophic phenotype, but knowledge gaps in the cause-effect of these processes are still present. In this review we will highlight the possible advantages and drawbacks of using this approach as a therapeutic strategy while focusing on the experimental models necessary for a better understanding of the phenomenon. Specifically, we will discuss in brief the cellular signaling pathways associated with the onset of a hypertrophic phenotype in chondrocytes during the progression of OA and will analyze in depth the advantages and disadvantages of various models that have been used to mimic it. Afterwards, we will present the strategies developed and proposed to impede chondrocyte hypertrophy and cartilage matrix mineralization/calcification. Finally, we will examine the future perspectives of OA therapeutic strategies.
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Mohd Yunus MH, Lee Y, Nordin A, Chua KH, Bt Hj Idrus R. Remodeling Osteoarthritic Articular Cartilage under Hypoxic Conditions. Int J Mol Sci 2022; 23:ijms23105356. [PMID: 35628163 PMCID: PMC9141680 DOI: 10.3390/ijms23105356] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 05/07/2022] [Accepted: 05/08/2022] [Indexed: 12/12/2022] Open
Abstract
Osteoarthritis (OA) is one of the leading joint diseases induced by abnormalities or inflammation in the synovial membrane and articular cartilage, causing severe pain and disability. Along with the cartilage malfunction, imbalanced oxygen uptake occurs, changing chondrocytes into type I collagen- and type X collagen-producing dedifferentiated cells, contributing to OA progression. However, mounting evidence suggests treating OA by inducing a hypoxic environment in the articular cartilage, targeting the inhibition of several OA-related pathways to bring chondrocytes into a normal state. This review discusses the implications of OA-diseased articular cartilage on chondrocyte phenotypes and turnover and debates the hypoxic mechanism of action. Furthermore, this review highlights the new understanding of OA, provided by tissue engineering and a regenerative medicine experimental design, modeling the disease into diverse 2D and 3D structures and investigating hypoxia and hypoxia-inducing biomolecules and potential cell therapies. This review also reports the mechanism of hypoxic regulation and highlights the importance of activating and stabilizing the hypoxia-inducible factor and related molecules to protect chondrocytes from mitochondrial dysfunction and apoptosis occurring under the influence of OA.
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Affiliation(s)
- Mohd Heikal Mohd Yunus
- Department of Physiology, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (K.H.C.); (R.B.H.I.)
- Correspondence: ; Tel.: +603-9145-8624
| | - Yemin Lee
- MedCentral Consulting, Jalan 27/117A, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (Y.L.); (A.N.)
| | - Abid Nordin
- MedCentral Consulting, Jalan 27/117A, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia; (Y.L.); (A.N.)
| | - Kien Hui Chua
- Department of Physiology, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (K.H.C.); (R.B.H.I.)
| | - Ruszymah Bt Hj Idrus
- Department of Physiology, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (K.H.C.); (R.B.H.I.)
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Zaki S, Blaker CL, Little CB. OA foundations - experimental models of osteoarthritis. Osteoarthritis Cartilage 2022; 30:357-380. [PMID: 34536528 DOI: 10.1016/j.joca.2021.03.024] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/01/2021] [Accepted: 03/10/2021] [Indexed: 02/02/2023]
Abstract
Osteoarthritis (OA) is increasingly recognised as a disease of diverse phenotypes with variable clinical presentation, progression, and response to therapeutic intervention. This same diversity is readily apparent in the many animal models of OA. However, model selection, study design, and interpretation of resultant findings, are not routinely done in the context of the target human (or veterinary) patient OA sub-population or phenotype. This review discusses the selection and use of animal models of OA in discovery and therapeutic-development research. Beyond evaluation of the different animal models on offer, this review suggests focussing the approach to OA-animal model selection on study objective(s), alignment of available models with OA-patient sub-types, and the resources available to achieve valid and translatable results. How this approach impacts model selection is discussed and an experimental design checklist for selecting the optimal model(s) is proposed. This approach should act as a guide to new researchers and a reminder to those already in the field, as to issues that need to be considered before embarking on in vivo pre-clinical research. The ultimate purpose of using an OA animal model is to provide the best possible evidence if, how, when and where a molecule, pathway, cell or process is important in clinical disease. By definition this requires both model and study outcomes to align with and be predictive of outcomes in patients. Keeping this at the forefront of research using pre-clinical OA models, will go a long way to improving the quality of evidence and its translational value.
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Affiliation(s)
- S Zaki
- Sydney School of Veterinary Science, Faculty of Science, University of Sydney, Australia; Raymond Purves Bone and Joint Research Laboratory, Australia.
| | - C L Blaker
- Raymond Purves Bone and Joint Research Laboratory, Australia; Murray Maxwell Biomechanics Laboratory, The Kolling Institute, University of Sydney Faculty of Medicine and Health, At Royal North Shore Hospital, Australia.
| | - C B Little
- Raymond Purves Bone and Joint Research Laboratory, Australia.
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Alves JC, Santos A, Jorge P, Lavrador C, Carreira LM. Intraarticular triamcinolone hexacetonide, stanozolol, Hylan G-F 20 and platelet concentrate in a naturally occurring canine osteoarthritis model. Sci Rep 2021; 11:3118. [PMID: 33542412 PMCID: PMC7862601 DOI: 10.1038/s41598-021-82795-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 01/25/2021] [Indexed: 01/30/2023] Open
Abstract
Osteoarthritis (OA) is a disease transversal to all mammals, a source of chronic pain and disability, a huge burden to societies, with a significant toll in healthcare cost, while reducing productivity and quality of life. The dog is considered a useful model for the translational study of the disease, closely matching human OA, with the advantage of a faster disease progression while maintaining the same life stages. In a prospective, longitudinal, double-blinded, negative controlled study, one hundred (N = 100) hip joints were selected and randomly assigned to five groups: control group (CG, n = 20, receiving a saline injection), triamcinolone hexacetonide group (THG, n = 20), platelet concentrate group (PCG, n = 20), stanozolol group (SG, n = 20) and hylan G-F 20 group (HG). Evaluations were conducted on days 0 (T0, treatment day), 8, 15, 30, 60, 90, 120, 150 and 180 days post-treatment, consisting of weight distribution analysis and data from four Clinical Metrology Instruments (CMI). Kaplan-Meier estimators were generated and compared with the Breslow test. Cox proportional hazard regression analysis was used to investigate the influence of variables of interest on treatment survival. All results were analyzed with IBM SPSS Statistics version 20 and a significance level of p < 0.05 was set. Sample included joints of 100 pelvic limbs (of patients with a mean age of 6.5 ± 2.4 years and body weight of 26.7 ± 5.2 kg. Joints were graded as mild (n = 70), moderate (n = 20) and severe (n = 10) OA. No differences were found between groups at T0. Kaplan-Meier analysis showed that all treatments produced longer periods with better results in the various evaluations compared to CG. Patients in HG and PCG took longer to return to baseline values and scores. A higher impact on pain interference was observed in THG, with a 95% improvement over CG. PCG and HG experienced 57-81% improvements in functional evaluation and impairments due to OA, and may be a better options for these cases. This study documented the efficacy of several approaches to relieve OA clinical signs. These approaches varied in intensity and duration. HG and PCG where the groups were more significant improvements were observed throughout the follow-up periods, with lower variation in results.
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Affiliation(s)
- J C Alves
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Rua Presidente Arriaga, 9, 1200-771, Lisbon, Portugal.
- MED - Mediterranean Institute for Agriculture, Environment and Development, Instituto de Investigação e Formação Avançada, Universidade de Évora, Pólo da Mitra, Ap. 94, 7006-554, Évora, Portugal.
| | - A Santos
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Rua Presidente Arriaga, 9, 1200-771, Lisbon, Portugal
| | - P Jorge
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Rua Presidente Arriaga, 9, 1200-771, Lisbon, Portugal
| | - C Lavrador
- MED - Mediterranean Institute for Agriculture, Environment and Development, Instituto de Investigação e Formação Avançada, Universidade de Évora, Pólo da Mitra, Ap. 94, 7006-554, Évora, Portugal
| | - L Miguel Carreira
- Faculty of Veterinary Medicine, University of Lisbon (FMV/ULisboa), Lisbon, Portugal
- Interdisciplinary Centre for Research in Animal Health (CIISA) - University of Lisbon, (FMV/ULisboa), Lisbon, Portugal
- Anjos of Assis Veterinary Medicine Centre (CMVAA), Barreiro, Portugal
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Alves JC, Santos A, Jorge P, Lavrador C, Carreira LM. The intra-articular administration of triamcinolone hexacetonide in the treatment of osteoarthritis. Its effects in a naturally occurring canine osteoarthritis model. PLoS One 2021; 16:e0245553. [PMID: 33471857 PMCID: PMC7816979 DOI: 10.1371/journal.pone.0245553] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 01/03/2021] [Indexed: 01/15/2023] Open
Abstract
OBJECTIVE To evaluate the effect of an intra-articular (IA) administration of triamcinolone hexacetonide, compared with saline. PATIENTS AND METHODS Forty (N = 40) hip joints were randomly assigned to a treatment group (THG, n = 20, receiving IA triamcinolone hexacetonide) and a control group (CG, n = 20, receiving IA saline). On treatment day (T0), and at 8, 15, 30, 90 and 180 days post-treatment, weight distribution, joint range of motion, thigh girth, digital thermography, radiographic signs, synovial fluid interleukin-1 and C-reactive protein levels were evaluated. Data from four Clinical Metrology Instruments was also gathered. Results were compared Repeated Measures ANOVA, with a Huynh-Feldt correction, Paired Samples T-Test or Wilcoxon Signed Ranks Test. A Kaplan-Meier test was performed to compare both groups, with p<0.05. RESULTS Joints were graded as mild (65%), moderate (20%) and severe (15%). Patients of both sexes, with a mean age of 6.5±2.4 years and bodyweight of 26.7±5.2kg, were included. No differences were found between groups at T0. Comparing THG to CG, weight distribution showed significant improvements in THG from 8 (p = 0.05) up to 90 days (p = 0.01). THG showed lower values during thermographic evaluation in the Lt view (p<0.01). Pain and function scores also improved from 30 to 180 days. Increasing body weight, age, and presence of caudolateral curvilinear osteophyte corresponded to worse response to treatment. Results of the Kaplan Meier test showed significant differences between groups, with THG performing better considering several evaluations and scores. CONCLUSION THG recorded significant improvements in weight-bearing and in with the considered CMIs, particularly pain scores. Lower thermographic values were registered in THG up to the last evaluation day. Age, sex, and radiographic findings did significantly influenced response to treatment.
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Affiliation(s)
- João C. Alves
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Lisbon, Portugal
- MED – Mediterranean Institute for Agriculture, Environment and Development, Instituto de Investigação e Formação Avançada, Universidade de Évora, Pólo da Mitra, Évora, Portugal
| | - Ana Santos
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Lisbon, Portugal
| | - Patrícia Jorge
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Lisbon, Portugal
| | - Catarina Lavrador
- MED – Mediterranean Institute for Agriculture, Environment and Development, Instituto de Investigação e Formação Avançada, Universidade de Évora, Pólo da Mitra, Évora, Portugal
| | - L. Miguel Carreira
- Faculty of Veterinary Medicine, University of Lisbon (FMV/ULisboa), Lisbon, Portugal
- Interdisciplinary Centre for Research in Animal Health (CIISA) – University of Lisbon, (FMV/ULisboa), Lisbon, Portugal
- Anjos of Assis Veterinary Medicine Centre (CMVAA), Barreiro, Portugal
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Oh J, Son YS, Kim WH, Kwon OK, Kang BJ. Mesenchymal stem cells genetically engineered to express platelet-derived growth factor and heme oxygenase-1 ameliorate osteoarthritis in a canine model. J Orthop Surg Res 2021; 16:43. [PMID: 33430899 PMCID: PMC7802278 DOI: 10.1186/s13018-020-02178-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 12/25/2020] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are used for the treatment of osteoarthritis (OA), and MSC genetic engineering is expected to enhance cartilage repair. Here, we aimed to investigate the effect of MSCs overexpressing platelet-derived growth factor (PDGF) or heme oxygenase-1 (HO-1) in chondrocytes and synovial cells with an OA phenotype and assess the in vivo efficacy of intra-articular injections of these MSCs in canine OA models. METHODS Canine adipose-derived MSCs were transfected with canine PDGF (PDGF-MSCs) or HO-1 (HO-1-MSCs) using lentiviral vectors. Canine chondrocytes or synovial cells were stimulated with lipopolysaccharide (LPS) to mimic the inflammatory OA model and then co-cultured with MSCs, PDGF-MSCs, or HO-1-MSCs for 24 h and 72 h. The mRNA levels of pro-inflammatory, extracellular matrix-degradative/synthetic, or pain-related factors were measured after co-culture by real-time PCR. Furthermore, a surgery-induced canine OA model was established and the dogs were randomized into four groups: normal saline (n = 4), MSCs (n = 4), PDGF-MSCs (n = 4), and HO-1-MSCs (n = 4). The OA symptoms, radiographic OA severity, and serum matrix metallopeptidase (MMP)-13 levels were assessed before and 10 weeks after treatment, to evaluate the safety and efficacy of the modified MSCs. RESULTS PDGF or HO-1 overexpression significantly reduced the expression of pro-inflammatory factors, MMP-13, and nerve growth factor elicited by LPS and increased that of aggrecan and collagen type 2 in chondrocytes (P < 0.05). In addition, the expression of aggrecanases was significantly downregulated in synovial cells, whereas that of tissue inhibitor of metalloproteinases was upregulated (P < 0.05). Furthermore, the co-cultured MSCs highly expressed genes that contributed to the maintenance of joint homeostasis (P < 0.05). In vivo studies showed that OA symptoms improved after administration of all MSCs. Also, PDGF-MSCs significantly improved limb function and reduced pain (P < 0.05). The results of the radiographic assessment and serum MMP-13 levels did not vary significantly compared to those of the control. CONCLUSIONS Genetically modifying PDGF and HO-1 in MSCs is an effective strategy for treating OA, suggesting that PDGF-MSCs can be novel therapeutic agents for improving OA symptoms.
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Affiliation(s)
- Jiwon Oh
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea
| | - Yeon Sung Son
- Medical Research Center, College of Medicine, Seoul National University, Seoul, 03080, South Korea
| | - Wan Hee Kim
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea
| | - Oh-Kyeong Kwon
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea
| | - Byung-Jae Kang
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, South Korea. .,BK21 PLUS Creative Veterinary Research Center, Seoul National University, Seoul, 08826, South Korea.
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Readioff R, Geraghty B, Elsheikh A, Comerford E. Viscoelastic characteristics of the canine cranial cruciate ligament complex at slow strain rates. PeerJ 2020; 8:e10635. [PMID: 33391887 PMCID: PMC7761198 DOI: 10.7717/peerj.10635] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 12/02/2020] [Indexed: 11/20/2022] Open
Abstract
Ligaments including the cruciate ligaments support and transfer loads between bones applied to the knee joint organ. The functions of these ligaments can get compromised due to changes to their viscoelastic material properties. Currently there are discrepancies in the literature on the viscoelastic characteristics of knee ligaments which are thought to be due to tissue variability and different testing protocols. The aim of this study was to characterise the viscoelastic properties of healthy cranial cruciate ligaments (CCLs), from the canine knee (stifle) joint, with a focus on the toe region of the stress-strain properties where any alterations in the extracellular matrix which would affect viscoelastic properties would be seen. Six paired CCLs, from skeletally mature and disease-free Staffordshire bull terrier stifle joints were retrieved as a femur-CCL-tibia complex and mechanically tested under uniaxial cyclic loading up to 10 N at three strain rates, namely 0.1%, 1% and 10%/min, to assess the viscoelastic property of strain rate dependency. The effect of strain history was also investigated by subjecting contralateral CCLs to an ascending (0.1%, 1% and 10%/min) or descending (10%, 1% and 0.1%/min) strain rate protocol. The differences between strain rates were not statistically significant. However, hysteresis and recovery of ligament lengths showed some dependency on strain rate. Only hysteresis was affected by the test protocol and lower strain rates resulted in higher hysteresis and lower recovery. These findings could be explained by the slow process of uncrimping of collagen fibres and the contribution of proteoglycans in the ligament extracellular matrix to intra-fibrillar gliding, which results in more tissue elongations and higher energy dissipation. This study further expands our understanding of canine CCL behaviour, providing data for material models of femur-CCL-tibia complexes, and demonstrating the challenges for engineering complex biomaterials such as knee joint ligaments.
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Affiliation(s)
- Rosti Readioff
- School of Engineering, University of Liverpool, Liverpool, UK
| | - Brendan Geraghty
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Ahmed Elsheikh
- School of Engineering, University of Liverpool, Liverpool, UK.,Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing, China.,UCL Institute of Ophthalmology, NIHR Moorfields BRC, London, UK
| | - Eithne Comerford
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.,School of Veterinary Science, University of Liverpool, Neston, UK
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Malek S, Weng HY, Martinson SA, Rochat MC, Béraud R, Riley CB. Evaluation of serum MMP-2 and MMP-3, synovial fluid IL-8, MCP-1, and KC concentrations as biomarkers of stifle osteoarthritis associated with naturally occurring cranial cruciate ligament rupture in dogs. PLoS One 2020; 15:e0242614. [PMID: 33211763 PMCID: PMC7676649 DOI: 10.1371/journal.pone.0242614] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 11/06/2020] [Indexed: 11/19/2022] Open
Abstract
The purpose of this study was to evaluate matrix metalloproteinases (MMP) -2 and MMP-3 in serum, and keratinocyte-derived chemoattractant (KC), interleukin 8 (IL-8) and monocyte chemoattractant 1 (MCP-1) in synovial fluid (SF) as stifle osteoarthritis (OA) biomarkers in dogs. Dogs with naturally occurring cranial cruciate ligament (CrCL) rupture (OA group) and healthy controls were recruited. Stifles with CrCL deficiency were surgically stabilized. Serum, SF, and synovial biopsy samples were collected from the OA group preoperatively, whereas samples were collected once from control dogs. A blinded veterinary pathologist graded synovial biopsies. Serum and SF analyses were performed using xMAP technology. General linear regression was used for statistical comparisons of serum biomarkers, and mixed linear regression for SF biomarkers and temporal concentration changes. The overall discriminative ability was quantified using area under curve (AUC). Spearman's correlation coefficient was used to assess correlations between synovial histology grades and the biomarkers. Samples from 62 dogs in the OA group and 50 controls were included. The MMP-2 and MMP-3 concentrations between the OA and control groups were not significantly different, and both with an AUC indicating a poor discriminative ability. All three SF biomarker concentrations were significantly different between the OA group and controls (P <0.05). The MCP-1 was the only biomarker showing an acceptable discriminative performance with an AUC of 0.91 (95% confidence interval: 0.83-0.98). The sum of the inflammatory infiltrate score was significantly correlated with all three SF biomarkers (P <0.01). Summed synovial stroma, and all scores combined were significantly correlated with IL-8 and MCP-1 concentrations (P <0.003), and the summed synoviocyte scores were significantly correlated with MCP-1 concentrations (P <0.001). Correlations between MCP-1 concentrations and synovial histopathologic grading and its discriminative ability suggest its potential as a synovitis biomarker in canine stifle OA associated with CrCL rupture.
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Affiliation(s)
- Sarah Malek
- Department of Veterinary Clinical Sciences, Purdue University School of Veterinary Medicine, West Lafayette, Indiana, United States of America
- * E-mail:
| | - Hsin-Yi Weng
- Department of Comparative Pathobiology, Purdue University School of Veterinary Medicine, West Lafayette, Indiana, United States of America
| | - Shannon A. Martinson
- Department of Pathology and Microbiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Mark C. Rochat
- Department of Veterinary Clinical Sciences, Purdue University School of Veterinary Medicine, West Lafayette, Indiana, United States of America
| | - Romain Béraud
- Centre Vétérinaire Daubigny, Quebec City, Quebec, Canada
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Alves JC, Santos A, Jorge P, Lavrador C, Carreira LM. A Pilot Study on the Efficacy of a Single Intra-Articular Administration of Triamcinolone Acetonide, Hyaluronan, and a Combination of Both for Clinical Management of Osteoarthritis in Police Working Dogs. Front Vet Sci 2020; 7:512523. [PMID: 33282924 PMCID: PMC7690322 DOI: 10.3389/fvets.2020.512523] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 10/12/2020] [Indexed: 01/15/2023] Open
Abstract
Objectives: To describe and compare the use and effectiveness of a single intra-articular injection (IA) of triamcinolone acetonide (TA), hyaluronan (HA), and a combination of both (TA+HA) in police working dogs with natural occurring hip osteoarthritis (OA). Study Design: Prospective, randomized, single-blinded study. Sample Population: Thirty animals with naturally occurring hip OA. Methods: Animals were randomly divided in three groups: GT, treated with 20 mg of TA per hip joint; GH, treated with treated 20 mg of HA per hip joint; and GTH, treated with a combination of 20 mg of TA and 20 mg of HA per hip joint. Response to treatment, measured by the Canine Brief Pain Inventory (divided in Pain Interference Score-PIS and Pain Severity Score-PSS) and the Hudson Visual Analog Scale (HVAS), was evaluated in seven different time points: T0 (before treatment), T1 (after 15 days), T2, T3, T4, T5, and T6 (after 1, 2, 3, 4, and 5 months, respectively). Results were compared using a Kruskal-Wallis test or a Wilcoxon signed ranks test, and p < 0.05 was set. Results: Comparing results of the different time points considered with T0, significant differences were registered in GH at T1 for HVAS (p = 0.03) and PIS (p = 0.04); and in GTH at T1 (p = 0.05 for HVAS and p < 0.05 for PIS), T2 (p < 0.04 for PIS), T3 (p < 0.03 for HVAS and p = 0.05 for PIS), T4 (p < 0.03 for HVAS and p < 0.05), and T5 (p < 0.05 for HVAS). No significant differences were found between groups when comparing scores in each time point. Individual treatment is considered successful with a reduction of ≥1 for PSS or ≥2 for PIS. In GTH, treatment was successful in four animals between T1 and T5 (40%, n = 10) and three at T6-T7 (30%, n = 10) for PSS and three animals of GTH at T1 (30%), two at T2 (20%), three between T3 and T4 (30%), and two between T5 and T7 (20%). Conclusions and Clinical Relevance: This study provides direct information on the use of these treatment modalities in patients with hip OA. Intra-articular injection with TA and HA may be a treatment option for dogs with naturally occurring OA, particularly when simultaneously used, as they provide significant improvements of PIS and HVAS scores. Individual scores improved in some animals with PIS, PSS, and HVAS.
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Affiliation(s)
- João C. Alves
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Lisbon, Portugal
- MED—Mediterranean Institute for Agriculture, Environment and Development, Instituto de Investigação e Formação Avançada, Universidade de Évora, Évora, Portugal
| | - Ana Santos
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Lisbon, Portugal
| | - Patrícia Jorge
- Divisão de Medicina Veterinária, Guarda Nacional Republicana (GNR), Lisbon, Portugal
| | - Catarina Lavrador
- MED—Mediterranean Institute for Agriculture, Environment and Development, Instituto de Investigação e Formação Avançada, Universidade de Évora, Évora, Portugal
| | - L. Miguel Carreira
- Faculty of Veterinary Medicine, University of Lisbon (FMV/ULisboa), Lisbon, Portugal
- Interdisciplinary Centre for Research in Animal Health (CIISA), University of Lisbon (FMV/ULisboa), Lisbon, Portugal
- Anjos of Assis Veterinary Medicine Centre (CMVAA), Barreiro, Portugal
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11
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Verrico CD, Wesson S, Konduri V, Hofferek CJ, Vazquez-Perez J, Blair E, Dunner K, Salimpour P, Decker WK, Halpert MM. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain 2020; 161:2191-2202. [PMID: 32345916 PMCID: PMC7584779 DOI: 10.1097/j.pain.0000000000001896] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/16/2020] [Indexed: 01/01/2023]
Abstract
ABSTRACT Over the last 2 decades, affirmative diagnoses of osteoarthritis (OA) in the United States have tripled due to increasing rates of obesity and an aging population. Hemp-derived cannabidiol (CBD) is the major nontetrahydrocannabinol component of cannabis and has been promoted as a potential treatment for a wide variety of disparate inflammatory conditions. Here, we evaluated CBD for its ability to modulate the production of proinflammatory cytokines in vitro and in murine models of induced inflammation and further validated the ability of a liposomal formulation to increase bioavailability in mice and in humans. Subsequently, the therapeutic potential of both naked and liposomally encapsulated CBD was explored in a 4-week, randomized placebo-controlled, double-blinded study in a spontaneous canine model of OA. In vitro and in mouse models, CBD significantly attenuated the production of proinflammatory cytokines IL-6 and TNF-α while elevating levels of anti-inflammatory IL-10. In the veterinary study, CBD significantly decreased pain and increased mobility in a dose-dependent fashion among animals with an affirmative diagnosis of OA. Liposomal CBD (20 mg/day) was as effective as the highest dose of nonliposomal CBD (50 mg/day) in improving clinical outcomes. Hematocrit, comprehensive metabolic profile, and clinical chemistry indicated no significant detrimental impact of CBD administration over the 4-week analysis period. This study supports the safety and therapeutic potential of hemp-derived CBD for relieving arthritic pain and suggests follow-up investigations in humans are warranted.
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Affiliation(s)
- Chris D. Verrico
- Department of Psychiatry, Baylor College of Medicine, Houston TX 77030
- Department of Pharmacology, Baylor College of Medicine, Houston TX 77030
| | | | - Vanaja Konduri
- Department of Pathology & Immunology, Baylor College of Medicine, Houston TX 77030
| | - Colby J. Hofferek
- Department of Pathology & Immunology, Baylor College of Medicine, Houston TX 77030
| | | | | | - Kenneth Dunner
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston TX 77030
| | | | - William K. Decker
- Department of Pathology & Immunology, Baylor College of Medicine, Houston TX 77030
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX 77030
- Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston TX 77030
| | - Matthew M. Halpert
- Department of Pathology & Immunology, Baylor College of Medicine, Houston TX 77030
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12
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Perry J, McCarthy HS, Bou-Gharios G, van 't Hof R, Milner PI, Mennan C, Roberts S. Injected human umbilical cord-derived mesenchymal stromal cells do not appear to elicit an inflammatory response in a murine model of osteoarthritis. OSTEOARTHRITIS AND CARTILAGE OPEN 2020; 2:100044. [PMID: 32596691 PMCID: PMC7307639 DOI: 10.1016/j.ocarto.2020.100044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 02/07/2020] [Indexed: 01/08/2023] Open
Abstract
Objective This study investigated the effect of hUC-MSCs on osteoarthritis (OA) progression in a xenogeneic model. Design Male, 10 week-old C57BL/6 mice underwent sham surgery (n = 15) or partial medial meniscectomy (PMM; n = 76). 5x105 hUC-MSCs (from 3 donors: D1, D2 and D3) were phenotyped via RT-qPCR and immunoprofiling their response to inflammatory stimuli. They were injected into the mouse joints 3 and 6 weeks post-surgery, harvesting joints at 8 and 12 weeks post-surgery, respectively. A no cell ‘control’ group was also used (n = 29). All knee joints were assessed via micro-computed tomography (μCT) and histology and 10 plasma markers were analysed at 12 weeks. Results PMM resulted in cartilage loss and osteophyte formation resembling human OA at both time-points. Injection of one donor's hUC-MSCs into the joint significantly reduced the loss of joint space at 12 weeks post-operatively compared with the PMM control. This ‘effective’ population of MSCs up-regulated the genes, IDO and TSG6, when stimulated with inflammatory cytokines, more than those from the other two donors. No evidence of an inflammatory response to the injected cells in any animals, either histologically or with plasma biomarkers, arose. Conclusion Beneficial change in a PMM joint was seen with only one hUC-MSC population, perhaps indicating that cell therapy is not appropriate for severely osteoarthritic joints. However, none of the implanted cells appeared to elicit an inflammatory response at the time-points studied. The variability of UC donors suggests some populations may be more therapeutic than others and donor characterisation is essential in developing allogeneic cell therapies.
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Affiliation(s)
- J Perry
- Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, SY10 7AG, UK.,School of Pharmacy and Bioengineering (PhaB), Keele University, Keele, ST4 7QB, UK
| | - H S McCarthy
- Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, SY10 7AG, UK.,School of Pharmacy and Bioengineering (PhaB), Keele University, Keele, ST4 7QB, UK
| | - G Bou-Gharios
- Institute of Ageing and Chronic Disease, University of Liverpool, L7 8TX, UK
| | - R van 't Hof
- Institute of Ageing and Chronic Disease, University of Liverpool, L7 8TX, UK
| | - P I Milner
- Institute of Ageing and Chronic Disease, University of Liverpool, L7 8TX, UK
| | - C Mennan
- Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, SY10 7AG, UK.,School of Pharmacy and Bioengineering (PhaB), Keele University, Keele, ST4 7QB, UK
| | - S Roberts
- Robert Jones & Agnes Hunt Orthopaedic Hospital NHS Foundation Trust, Oswestry, SY10 7AG, UK.,School of Pharmacy and Bioengineering (PhaB), Keele University, Keele, ST4 7QB, UK
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13
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Meeson RL, Todhunter RJ, Blunn G, Nuki G, Pitsillides AA. Spontaneous dog osteoarthritis - a One Medicine vision. Nat Rev Rheumatol 2020; 15:273-287. [PMID: 30953036 PMCID: PMC7097182 DOI: 10.1038/s41584-019-0202-1] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Osteoarthritis (OA) is a global disease that, despite extensive research, has limited treatment options. Pet dogs share both an environment and lifestyle attributes with their owners, and a growing awareness is developing in the public and among researchers that One Medicine, the mutual co-study of animals and humans, could be beneficial for both humans and dogs. To that end, this Review highlights research opportunities afforded by studying dogs with spontaneous OA, with a view to sharing this active area of veterinary research with new audiences. Similarities and differences between dog and human OA are examined, and the proposition is made that suitably aligned studies of spontaneous OA in dogs and humans, in particular hip and knee OA, could highlight new avenues of discovery. Developing cross-species collaborations will provide a wealth of research material and knowledge that is relevant to human OA and that cannot currently be obtained from rodent models or experimentally induced dog models of OA. Ultimately, this Review aims to raise awareness of spontaneous dog OA and to stimulate discussion regarding its exploration under the One Medicine initiative to improve the health and well-being of both species. Osteoarthritis occurs spontaneously in pet dogs, which often share environmental and lifestyle risk-factors with their owners. This Review aims to stimulate cooperation between medical and veterinary research under the One Medicine initiative to improve the welfare of dogs and humans.
Dogs have many analogous spontaneous diseases that result in end-stage osteoarthritis (OA). Inbreeding and the predisposition of certain dog breeds for OA enable easier identification of candidate genetic associations than in outbred humans. Dog OA subtypes offer a potential stratification rationale for aetiological differences and alignment to analogous human OA phenotypes. The relatively compressed time course of spontaneous dog OA offers longitudinal research opportunities. Collaboration with veterinary researchers can provide tissue samples from early-stage OA and opportunities to evaluate new therapeutics in a spontaneous disease model. Awareness of the limitations and benefits of using clinical veterinary patients in research is important.
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Affiliation(s)
- Richard L Meeson
- Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK.,Department of Clinical Services and Sciences, Royal Veterinary College, University of London, London, UK.,Institute of Orthopaedics and Musculoskeletal Science, University College London, London, UK
| | - Rory J Todhunter
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA.,Cornell Veterinary Biobank, Cornell University, Ithaca, NY, USA
| | - Gordon Blunn
- Institute of Orthopaedics and Musculoskeletal Science, University College London, London, UK.,School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - George Nuki
- Institute for Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Andrew A Pitsillides
- Skeletal Biology Group, Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, UK.
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14
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Infrared spectroscopy of serum as a potential diagnostic screening approach for naturally occurring canine osteoarthritis associated with cranial cruciate ligament rupture. Osteoarthritis Cartilage 2020; 28:231-238. [PMID: 31682906 DOI: 10.1016/j.joca.2019.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 10/16/2019] [Accepted: 10/18/2019] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To evaluate infrared (IR) spectroscopy of serum as a screening tool to differentiate dogs affected by naturally occurring osteoarthritis (OA) associated with cranial cruciate ligament rupture (CrCLR) and controls. METHOD 104 adult dogs with CrCLR (affected group) and 50 adult control dogs were recruited for this prospective observational study. Serum samples were collected preoperatively from CrCLR dogs and from a subset of these dogs at 4-, and 12-week post-surgical intervention to stabilize the affected stifles. Serum was collected once from control dogs. Dry films were made from serum samples, and IR absorbance spectra acquired. Data preprocessing, principal component analysis and multivariate analysis of covariance were performed to separate samples from the two groups, and to evaluate temporal differences. Weighted logistic regression with L1 regularization method was used to develop a predictive model. Model performance based on an independent test set was evaluated. RESULTS Spectral data analysis revealed significant separation between the sera of CrCLR and control dogs (P < 0.0001), but not amongst different time points in the OA group. The sensitivity, specificity, AUC and accuracy of the test set were 84.62%, 96.15%, 93.20% and 92.31% respectively. CONCLUSIONS These findings confirm the potential of IR-spectroscopy of serum with chemometrics methods to differentiate controls from dogs with OA associated with CrCLR. This is the first step in development of an economic, and comparatively simple IR-based screening serum test for OA. Utility of this tool as a clinical screening and diagnostic test requires further investigation and validation.
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15
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Macfadyen MA, Daniel Z, Kelly S, Parr T, Brameld JM, Murton AJ, Jones SW. The commercial pig as a model of spontaneously-occurring osteoarthritis. BMC Musculoskelet Disord 2019; 20:70. [PMID: 30744620 PMCID: PMC6371556 DOI: 10.1186/s12891-019-2452-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 02/01/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Preclinical osteoarthritis models where damage occurs spontaneously may better reflect the initiation and development of human osteoarthritis. The aim was to assess the commercial pig as a model of spontaneous osteoarthritis development by examining pain-associated behaviour, joint cartilage integrity, as well as the use of porcine cartilage explants and isolated chondrocytes and osteoblasts for ex vivo and in vitro studies. METHODS Female pigs (Large white x Landrace x Duroc) were examined at different ages from 6 weeks to 3-4 years old. Lameness was assessed as a marker of pain-associated behaviour. Femorotibial joint cartilage integrity was determined by chondropathy scoring and histological staining of proteoglycan. IL-6 production and proteoglycan degradation was assessed in cartilage explants and primary porcine chondrocytes by ELISA and DMMB assay. Primary porcine osteoblasts from damaged and non-damaged joints, as determined by chondropathy scoring, were assessed for mineralisation, proliferative and mitochondrial function as a marker of metabolic capacity. RESULTS Pigs aged 80 weeks and older exhibited lameness. Osteoarthritic lesions in femoral condyle and tibial plateau cartilage were apparent from 40 weeks and increased in severity with age up to 3-4 years old. Cartilage from damaged joints exhibited proteoglycan loss, which positively correlated with chondropathy score. Stimulation of porcine cartilage explants and primary chondrocytes with either IL-1β or visfatin induced IL-6 production and proteoglycan degradation. Primary porcine osteoblasts from damaged joints exhibited reduced proliferative, mineralisation, and metabolic capacity. CONCLUSION In conclusion, the commercial pig represents an alternative model of spontaneous osteoarthritis and an excellent source of tissue for in vitro and ex vivo studies.
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Affiliation(s)
- Mhairi A Macfadyen
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Biosciences, University of Nottingham, Sutton Bonington, UK
| | - Zoe Daniel
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Biosciences, University of Nottingham, Sutton Bonington, UK
| | - Sara Kelly
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Biosciences, University of Nottingham, Sutton Bonington, UK
| | - Tim Parr
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Biosciences, University of Nottingham, Sutton Bonington, UK
| | - John M Brameld
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Biosciences, University of Nottingham, Sutton Bonington, UK
| | - Andrew J Murton
- MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Biosciences, University of Nottingham, Sutton Bonington, UK.,Metabolism Unit, Shriners Hospitals for Children, Galveston, TX, USA.,Department of Surgery, University of Texas Medical Branch, Galveston, TX, USA
| | - Simon W Jones
- Institute of Inflammation and Ageing, MRC-ARUK Centre for Musculoskeletal Ageing Research, School of Immunity, University of Birmingham, Birmingham, UK.
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16
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Abstract
Osteochondral (OC) lesions are a major cause of chronic musculoskeletal pain and functional disability, which reduces the quality of life of the patients and entails high costs to the society. Currently, there are no effective treatments, so in vitro and in vivo disease models are critically important to obtain knowledge about the causes and to develop effective treatments for OC injuries. In vitro models are essential to clarify the causes of the disease and the subsequent design of the first barrier to test potential therapeutics. On the other hand, in vivo models are anatomically more similar to humans allowing to reproduce the pattern and progression of the lesion in a controlled scene and offering the opportunity to study the symptoms and responses to new treatments. Moreover, in vivo models are the most suitable preclinical model, being a fundamental and a mandatory step to ensure the successful transfer to clinical trials. Both in vitro and in vitro models have a number of advantages and limitation, and the choice of the most appropriate model for each study depends on many factors, such as the purpose of the study, handling or the ease to obtain, and cost, among others. In this chapter, we present the main in vitro and in vivo OC disease models that have been used over the years in the study of origin, progress, and treatment approaches of OC defects.
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17
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Bearden RN, Huggins SS, Cummings KJ, Smith R, Gregory CA, Saunders WB. In-vitro characterization of canine multipotent stromal cells isolated from synovium, bone marrow, and adipose tissue: a donor-matched comparative study. Stem Cell Res Ther 2017; 8:218. [PMID: 28974260 PMCID: PMC5627404 DOI: 10.1186/s13287-017-0639-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 07/06/2017] [Accepted: 07/24/2017] [Indexed: 12/14/2022] Open
Abstract
Background The dog represents an excellent large animal model for translational cell-based studies. Importantly, the properties of canine multipotent stromal cells (cMSCs) and the ideal tissue source for specific translational studies have yet to be established. The aim of this study was to characterize cMSCs derived from synovium, bone marrow, and adipose tissue using a donor-matched study design and a comprehensive series of in-vitro characterization, differentiation, and immunomodulation assays. Methods Canine MSCs were isolated from five dogs with cranial cruciate ligament rupture. All 15 cMSC preparations were evaluated using colony forming unit (CFU) assays, flow cytometry analysis, RT-PCR for pluripotency-associated genes, proliferation assays, trilineage differentiation assays, and immunomodulation assays. Data were reported as mean ± standard deviation and compared using repeated-measures analysis of variance and Tukey post-hoc test. Significance was established at p < 0.05. Results All tissue samples produced plastic adherent, spindle-shaped preparations of cMSCs. Cells were negative for CD34, CD45, and STRO-1 and positive for CD9, CD44, and CD90, whereas the degree to which cells were positive for CD105 was variable depending on tissue of origin. Cells were positive for the pluripotency-associated genes NANOG, OCT4, and SOX2. Accounting for donor and tissue sources, there were significant differences in CFU potential, rate of proliferation, trilineage differentiation, and immunomodulatory response. Synovium and marrow cMSCs exhibited superior early osteogenic activity, but when assessing late-stage osteogenesis no significant differences were detected. Interestingly, bone morphogenic protein-2 (BMP-2) supplementation was necessary for early-stage and late-stage osteogenic differentiation, a finding consistent with other canine studies. Additionally, synovium and adipose cMSCs proliferated more rapidly, displayed higher CFU potential, and formed larger aggregates in chondrogenic assays, although proteoglycan and collagen type II staining were subjectively decreased in adipose pellets as compared to synovial and marrow pellets. Lastly, cMSCs derived from all three tissue sources modulated murine macrophage TNF-α and IL-6 levels in a lipopolysaccharide-stimulated coculture assay. Conclusions While cMSCs from synovium, marrow, and adipose tissue share a number of similarities, important differences in proliferation and trilineage differentiation exist and should be considered when selecting cMSCs for translational studies. These results and associated methods will prove useful for future translational studies involving the canine model. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0639-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Robert N Bearden
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Shannon S Huggins
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Kevin J Cummings
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Roger Smith
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Carl A Gregory
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, College of Medicine, Texas A&M University, College Station, TX, USA
| | - William B Saunders
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
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18
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Vrancken ACT, Hannink G, Madej W, Verdonschot N, van Tienen TG, Buma P. In Vivo Performance of a Novel, Anatomically Shaped, Total Meniscal Prosthesis Made of Polycarbonate Urethane: A 12-Month Evaluation in Goats. Am J Sports Med 2017; 45:2824-2834. [PMID: 28719787 DOI: 10.1177/0363546517713687] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Injury or loss of the meniscus generally leads to degenerative osteoarthritic changes in the knee joint. However, the treatment options for symptomatic patients with total meniscectomy are limited. Therefore, we developed a novel, anatomically shaped, total meniscal implant made of polycarbonate urethane. PURPOSE To evaluate the in vivo performance of this novel total meniscal implant. The assessment particularly focused on the implant's response to long-term physiological loading in a goat model and its chondroprotective capacity in comparison to clinically relevant controls. STUDY DESIGN Controlled laboratory study. METHODS Surgery was performed to the stifle joint of 26 female Saanen goats, subdivided into 4 groups: implant, allograft, total meniscectomy, and sham surgery. The sham group's contralateral joints served as nonoperated controls. After 12 months of follow-up, investigators evaluated implant wear, deformation, and the histopathological condition of the synovium and cartilage. RESULTS Wear of the implant's articulating surfaces was minimal, which was confirmed by the absence of wear particles in the synovial fluid. Implant deformation was limited. However, one implant failed by complete tearing of the posterior horn extension. No differences in cartilage histopathological condition were observed for the implant, allograft, and meniscectomy groups. However, locally, the cartilage scores for these groups were significantly worse than those of the nonoperated controls. CONCLUSION Whereas this study demonstrated that the novel implant is resistant to wear and that deformation after 12 months of physiological loading is acceptable, reinforcement of the implant horns is necessary to prevent horn failure. Although the implant could not protect the cartilage from developing degenerative changes, the progression of damage was similar in the allograft group. CLINICAL RELEVANCE This novel polycarbonate urethane implant may have the potential to become an alternative treatment for symptomatic patients with total meniscectomy.
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Affiliation(s)
- Anne C T Vrancken
- Department of Orthopaedics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Gerjon Hannink
- Department of Orthopaedics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Wojciech Madej
- Department of Orthopaedics, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Nico Verdonschot
- Department of Orthopaedics, Radboud University Medical Center, Nijmegen, the Netherlands.,Laboratory of Biomechanical Engineering, University of Twente, Enschede, the Netherlands
| | - Tony G van Tienen
- Department of Orthopaedics, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Orthopaedic Surgery, Kliniek ViaSana, Mill, the Netherlands
| | - Pieter Buma
- Department of Orthopaedics, Radboud University Medical Center, Nijmegen, the Netherlands
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Shahid M, Manchi G, Slunsky P, Naseer O, Fatima A, Leo B, Raila J. A systemic review of existing serological possibilities to diagnose canine osteoarthritis with a particular focus on extracellular matrix proteoglycans and protein. Pol J Vet Sci 2017; 20:189-201. [PMID: 28525322 DOI: 10.1515/pjvs-2017-0024] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Extra-cellular matrix (ECM) components are important and their stabilization is significant in maintaining normal healthy joint environment. In osteoarthritis (OA), ECM components are altered and indicate disease progression. The joint ECM is composed of proteoglycans (aggrecan, perlecan, inter α-trypsin inhibitor), glycoproteins (fibronectin, lubricin, COMP) and collagen types (most abundantly collagen type II) which represent structural and functional transformation during disease advancement. ECM investigation revealed significant biomarkers of OA that could be used as a diagnostic and therapeutic tool in different canine orthopedic diseases. This review deliberates our current findings of how the components of ECM change at the molecular level during disease progression in canine OA.
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20
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Westermann RW, Jones M, Wasserstein D, Spindler KP. Clinical and radiographic outcomes of meniscus surgery and future targets for biologic intervention: A review of data from the MOON Group. Connect Tissue Res 2017; 58:366-372. [PMID: 28282214 PMCID: PMC5770978 DOI: 10.1080/03008207.2017.1297808] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Meniscus injury and treatment occurred with the majority of anterior cruciate ligament reconstructions (ACLR) in the multicenter orthopedic outcomes (MOON) cohort. We describe the patient-reported outcomes, radiographic outcomes, and predictors of pain from meniscus injuries and treatment in the setting of ACLR. Patient-reported outcomes improve significantly following meniscus repair with ACLR, but differences exist based on the meniscus injury laterally (medial or lateral). Patients undergoing medial meniscus repair have worse patient-reported outcomes and more pain compared to those with uninjured menisci. However, lateral meniscal tears can be repaired with similar outcomes as uninjured menisci. Medial meniscal treatment (meniscectomy or repair) results in a significant loss of joint space at 2 years compared to uninjured menisci. Menisci treated with excision had a greater degree of joint space loss compared to those treated with repair. Clinically significant knee pain is more common following injuries to the medial meniscus and increased in patients who undergo early re-operation after initial ACLR. Future research efforts aimed at improving outcomes after combined ACLR and meniscus treatment should focus on optimizing biologic and mechanical environments that promote healing of medial meniscal tears sustained during ACL injury.
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Reisig G, Kreinest M, Richter W, Wagner-Ecker M, Dinter D, Attenberger U, Schneider-Wald B, Fickert S, Schwarz ML. Osteoarthritis in the Knee Joints of Göttingen Minipigs after Resection of the Anterior Cruciate Ligament? Missing Correlation of MRI, Gene and Protein Expression with Histological Scoring. PLoS One 2016; 11:e0165897. [PMID: 27820852 PMCID: PMC5098790 DOI: 10.1371/journal.pone.0165897] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 10/19/2016] [Indexed: 12/14/2022] Open
Abstract
Introduction The Göttingen Minipig (GM) is used as large animal model in articular cartilage research. The aim of the study was to introduce osteoarthritis (OA) in the GM by resecting the anterior cruciate ligament (ACLR) according to Pond and Nuki, verified by histological and magnetic resonance imaging (MRI) scoring as well as analysis of gene and protein expression. Materials and Methods The eight included skeletally mature female GM were assessed after ACLR in the left and a sham operation in the right knee, which served as control. 26 weeks after surgery the knee joints were scanned using a 3-Tesla high-field MR tomography unit with a 3 T CP Large Flex Coil. Standard proton-density weighted fat saturated sequences in coronal and sagittal direction with a slice thickness of 3 mm were used. The MRI scans were assessed by two radiologists according to a modified WORMS-score, the X-rays of the knee joints by two evaluators. Osteochondral plugs with a diameter of 4mm were taken for histological examination from either the main loading zone or the macroscopic most degenerated parts of the tibia plateau or condyle respectively. The histological sections were blinded and scored by three experts according to Little et al. Gene expression analysis was performed from surrounding cartilage. Expression of adamts4, adamts5, acan, col1A1, col2, il-1ß, mmp1, mmp3, mmp13, vegf was determined by qRT-PCR. Immunohistochemical staining (IH) of Col I and II was performed. IH was scored using a 4 point grading (0—no staining; 3-intense staining). Results and Discussion Similar signs of OA were evident both in ACLR and sham operated knee joints with the histological scoring result of the ACLR joints with 6.48 ± 5.67 points and the sham joints with 6.86 ± 5.84 points (p = 0.7953) The MRI scoring yielded 0.34 ± 0.89 points for the ACLR and 0.03 ± 0.17 for the sham knee joints. There was no correlation between the histological and MRI scores (r = 0.10021). The gene expression profiles as well as the immunohistochemical findings showed no significant differences between ACLR and sham knee joints. In conclusion, both knee joints showed histological signs of OA after 26 weeks irrespective of whether the ACL was resected or not. As MRI results did not match the histological findings, MRI was obviously unsuitable to diagnose the OA in GM. The analysis of the expression patterns of the 10 genes could not shed light on the question, whether sham operation also induced cartilage erosion or if the degeneration was spontaneous. The modified Pond-Nuki model may be used with reservation in the adult minipig to induce an isolated osteoarthritis.
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Affiliation(s)
- Gregor Reisig
- Department for experimental Orthopaedics and Trauma Surgery, Orthopaedic and Trauma Surgery Centre (OUZ), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Michael Kreinest
- Department for experimental Orthopaedics and Trauma Surgery, Orthopaedic and Trauma Surgery Centre (OUZ), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Wiltrud Richter
- Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Heidelberg, Germany
| | - Mechthild Wagner-Ecker
- Research Centre for Experimental Orthopaedics, Orthopaedic University Hospital Heidelberg, Heidelberg, Germany
| | - Dietmar Dinter
- Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim, Germany
| | - Ulrike Attenberger
- Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Mannheim, Germany
| | - Barbara Schneider-Wald
- Department for experimental Orthopaedics and Trauma Surgery, Orthopaedic and Trauma Surgery Centre (OUZ), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Stefan Fickert
- Department for experimental Orthopaedics and Trauma Surgery, Orthopaedic and Trauma Surgery Centre (OUZ), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Markus L. Schwarz
- Department for experimental Orthopaedics and Trauma Surgery, Orthopaedic and Trauma Surgery Centre (OUZ), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- * E-mail:
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Coughlin TR, Kennedy OD. The role of subchondral bone damage in post-traumatic osteoarthritis. Ann N Y Acad Sci 2016; 1383:58-66. [DOI: 10.1111/nyas.13261] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 08/19/2016] [Accepted: 08/23/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Thomas R. Coughlin
- Department of Orthopedic Surgery; New York University School of Medicine; New York New York
| | - Oran D. Kennedy
- Department of Orthopedic Surgery; New York University School of Medicine; New York New York
- Department of Mechanical and Aerospace Engineering; New York University Tandon School of Engineering; New York New York
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Hamaia SW, Luff D, Hunter EJ, Malcor JD, Bihan D, Gullberg D, Farndale RW. Unique charge-dependent constraint on collagen recognition by integrin α10β1. Matrix Biol 2016; 59:80-94. [PMID: 27569273 PMCID: PMC5380659 DOI: 10.1016/j.matbio.2016.08.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 08/19/2016] [Accepted: 08/19/2016] [Indexed: 12/27/2022]
Abstract
The collagen-binding integrins recognise collagen through their inserted (I) domain, where co-ordination of a Mg2 + ion in the metal ion-dependent site is reorganised by ligation by a collagen glutamate residue found in specific collagen hexapeptide motifs. Here we show that GROGER, found in the N-terminal domain of collagens I and III, is only weakly recognised by α10β1, an important collagen receptor on chondrocytes, contrasting with the other collagen-binding integrins. Alignment of I domain sequence and molecular modelling revealed a clash between a unique arginine residue (R215) in α10β1 and the positively-charged GROGER. Replacement of R215 with glutamine restored binding. Substituting arginine at the equivalent locus (Q214) in integrins α1 and α2 I domains impaired their binding to GROGER. Collagen II, abundant in cartilage, lacks GROGER. GRSGET is uniquely expressed in the C-terminus of collagen II, but this motif is similarly not recognised by α10β1. These data suggest an evolutionary imperative to maintain accessibility of the terminal domains of collagen II in tissues such as cartilage, perhaps during endochondral ossification, where α10β1 is the main collagen-binding integrin.
Integrin α10β1 binding to collagen is mapped onto Collagen Toolkits. Charged residue in α10 I domain clashes with some binding sites that are unique to collagen II. Mutant constructs of other integrin I domains mimic this charge effect. Implications for evolution of collagens and cartilage with reference to bone formation
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Affiliation(s)
- Samir W Hamaia
- Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK
| | - Daisy Luff
- Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK
| | - Emma J Hunter
- Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK
| | - Jean-Daniel Malcor
- Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK
| | - Dominique Bihan
- Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK
| | - Donald Gullberg
- Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway
| | - Richard W Farndale
- Department of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, UK.
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Danshen prevents articular cartilage degeneration via antioxidation in rabbits with osteoarthritis. Osteoarthritis Cartilage 2016; 24:514-20. [PMID: 26485068 DOI: 10.1016/j.joca.2015.10.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 10/06/2015] [Accepted: 10/09/2015] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To evaluate the efficacy of Danshen on histological parameters and antioxidative activity in the articular cartilage of rabbits with osteoarthritis (OA). DESIGN Twenty-four rabbits were randomly divided into three groups (control, OA, and Danshen OA; eight rabbits per group). Anterior cruciate ligament transection (ACLT) of the left hind knees was performed in all rabbits in the OA and Danshen OA group for induction of OA. The rabbits in the control group underwent a sham operation. After surgery, 3 g/kg body weight of Danshen granules dissolved in 5 mL distilled water was administered by gastric intubation once per day and over a 6-week period to the Danshen OA group. The same volume of distilled water was administered to the OA and control groups. After 6 weeks, the medial femoral condyles and synoviums of the left hind knees in all three groups were harvested and used for histological and biochemical analyses. RESULTS Severe articular cartilage degeneration as well as lower proteoglycan (PG) content were noted in the OA group compared to the Danshen OA group (P < 0.05). The glutathione (GSH) levels in the synovium and articular cartilage of the rabbits in the Danshen OA group were significantly higher compared to the OA group (P < 0.001). The malondialdehyde (MDA) levels of the synovium and articular cartilage in the Danshen OA group was markedly depleted compared to the OA group (P < 0.001). CONCLUSION Danshen can prevent articular cartilage degeneration in OA through the defense against oxidative stress.
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Ni GX, Zhou YZ, Chen W, Xu L, Li Z, Liu SY, Lei L, Zhan LQ. Different responses of articular cartilage to strenuous running and joint immobilization. Connect Tissue Res 2015; 57:143-151. [PMID: 26631363 DOI: 10.3109/03008207.2015.1117457] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To compare the pathological changes in cartilage derived from rats that developed osteoarthritis either by joint immobilization or by strenuous treadmill running in order to better understand their respective pathomechanism. METHOD A total of 24 male Wistar rats were randomly assigned to three groups: sedentary control (CON), immobilization (IM), and strenuous running (SR). For rats in the IM group, unilateral knee joint was immobilized in flexion. Rats in the SR group underwent treadmill running with high intensity. Eight weeks later, all animals were sacrificed. Femoral condyles were collected to take histological observation for cartilage characteristic and immunohistochemistry for collagen type II. In addition, cartilage samples were obtained to assess gene expression of aggrecan, collagen type II, biglycan, and fibromodulin by quantitative RT-PCR. RESULTS Gross and histological observation showed osteoarthritic changes in groups SR and IM; however, more severe cartilage degradation was revealed in the latter. Proteoglycan and collagen II content decreased in groups SR and IM in comparison to group CON, with more loss in group IM. In group SR, mRNA levels in femoral cartilage were found to be unaltered for all the molecules measured. On the contrary, these molecules were significantly downregulated in group IM. CONCLUSION Differences in gross observation, histological characteristics, and gene expression of proteoglycans and collagen II suggest that both knee immobilization and strenuous running would lead to degenerative change of cartilage, but at different stages of the degenerative process.
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Affiliation(s)
- Guo-Xin Ni
- a Department of Rehabilitation Medicine, First Affiliated Hospital , Fujian Medical University , Fuzhou , China
| | - Yue-Zhu Zhou
- a Department of Rehabilitation Medicine, First Affiliated Hospital , Fujian Medical University , Fuzhou , China
| | - Wei Chen
- b Department of Physical Education , Fujian Medical University , Fuzhou , China
| | - Lei Xu
- c Department of Orthopaedics and Traumatology , Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Zhe Li
- c Department of Orthopaedics and Traumatology , Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Sheng-Yao Liu
- c Department of Orthopaedics and Traumatology , Nanfang Hospital, Southern Medical University , Guangzhou , China
| | - Lei Lei
- d Department of Rehabilitation Medicine , Longyan First Hospital , Longyan , China
| | - Li-Qiong Zhan
- a Department of Rehabilitation Medicine, First Affiliated Hospital , Fujian Medical University , Fuzhou , China
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Vrancken ACT, Madej W, Hannink G, Verdonschot N, van Tienen TG, Buma P. Short Term Evaluation of an Anatomically Shaped Polycarbonate Urethane Total Meniscus Replacement in a Goat Model. PLoS One 2015; 10:e0133138. [PMID: 26192414 PMCID: PMC4507942 DOI: 10.1371/journal.pone.0133138] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 06/23/2015] [Indexed: 11/22/2022] Open
Abstract
Purpose Since the treatment options for symptomatic total meniscectomy patients are still limited, an anatomically shaped, polycarbonate urethane (PCU), total meniscus replacement was developed. This study evaluates the in vivo performance of the implant in a goat model, with a specific focus on the implant location in the joint, geometrical integrity of the implant and the effect of the implant on synovial membrane and articular cartilage histopathological condition. Methods The right medial meniscus of seven Saanen goats was replaced by the implant. Sham surgery (transection of the MCL, arthrotomy and MCL suturing) was performed in six animals. The contralateral knee joints of both groups served as control groups. After three months follow-up the following aspects of implant performance were evaluated: implant position, implant deformation and the histopathological condition of the synovium and cartilage. Results Implant geometry was well maintained during the three month implantation period. No signs of PCU wear were found and the implant did not induce an inflammatory response in the knee joint. In all animals, implant fixation was compromised due to suture breakage, wear or elongation, likely causing the increase in extrusion observed in the implant group. Both the femoral cartilage and tibial cartilage in direct contact with the implant showed increased damage compared to the sham and sham-control groups. Conclusion This study demonstrates that the novel, anatomically shaped PCU total meniscal replacement is biocompatible and resistant to three months of physiological loading. Failure of the fixation sutures may have increased implant mobility, which probably induced implant extrusion and potentially stimulated cartilage degeneration. Evidently, redesigning the fixation method is necessary. Future animal studies should evaluate the improved fixation method and compare implant performance to current treatment standards, such as allografts.
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Affiliation(s)
- A C T Vrancken
- Radboud University Medical Center, Radboud Institute for Health Sciences, Orthopaedic Research Lab, Nijmegen, The Netherlands
| | - W Madej
- Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Orthopaedic Research Lab, Nijmegen, The Netherlands
| | - G Hannink
- Radboud University Medical Center, Radboud Institute for Health Sciences, Orthopaedic Research Lab, Nijmegen, The Netherlands
| | - N Verdonschot
- Radboud University Medical Center, Radboud Institute for Health Sciences, Orthopaedic Research Lab, Nijmegen, The Netherlands; Laboratory for Biomechanical Engineering, University of Twente, Enschede, The Netherlands
| | - T G van Tienen
- Radboud University Medical Center, Radboud Institute for Health Sciences, Orthopaedic Research Lab, Nijmegen, The Netherlands; Department of Orthopaedic Surgery, Via Sana Clinic, Mill, The Netherlands
| | - P Buma
- Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Orthopaedic Research Lab, Nijmegen, The Netherlands
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Cınar BM, Ozkoc G, Bolat F, Karaeminogullari O, Sezgin N, Tandogan RN. Intra-articular zoledronic acid in a rat osteoarthritis model: significant reduced synovitis may indicate chondroprotective effect. Knee Surg Sports Traumatol Arthrosc 2015; 23:1410-1418. [PMID: 24664185 DOI: 10.1007/s00167-014-2955-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Accepted: 03/12/2014] [Indexed: 11/24/2022]
Abstract
PURPOSE The aim of this experimental study was to evaluate the effect of intra-articular application of zoledronic acid (ZA) on joint cartilage and synovial tissue following induction of knee osteoarthritis (OA) in a rat model. METHODS An OA model was created by anterior cruciate ligament transection (ACLT) in the right knees of 48 adult Wistar albino rats. The rats were randomized into a study and control groups, each including 24 rats, and 10 μg of ZA was injected in 0.1 ml of sterile saline to 24 animals in the study group on the first day to operation and was repeated weekly until the rats were killed. The same volume of sterile saline was injected with the same schedule to the control group. Eight rats from both the study and control groups were killed, each time, on the 4th day, the 3rd week, and the 6th week after the operation. The groups were compared based on the histological scores of synovitis and cartilage destruction and the evaluation of serum markers. RESULTS Histological score indicates progression of synovitis was significantly less in the study group (p = 0.047). There was significant increase in the mean Mankin cartilage damage score in the control group (p = 0.021), while no significant change was found in the study group. When the two groups were compared over time, no statistically significant difference was detected in total histological scores, although there was a 47 % less incidence of cartilage tissue damage in the study group and better cartilage structure and tide mark integrity scores were also detected in the study group (p = 0.017 and p = 0.021, respectively). CONCLUSION Intra- articular zoledronic acid may suppress synovial inflammation. Furthermore, Zoledronic Acid does not reduce cartilage degeneration in early osteoarthritis models, but may provide some chondroprotective effect in ACLT- induced knee osteoarthritis model in rats.
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Affiliation(s)
- B Murat Cınar
- Department of Orthopedics and Traumatology, Adana Research and Clinic Center, Baskent University School of Medicine, Dadaloglu Mah.39.Sok. No: 6, Yuregir/Adana, 01250, Turkey.
| | - Gurkan Ozkoc
- Department of Orthopedics and Traumatology, Adana Research and Clinic Center, Baskent University School of Medicine, Dadaloglu Mah.39.Sok. No: 6, Yuregir/Adana, 01250, Turkey
| | - Filiz Bolat
- Department of Pathology, Baskent University School of Medicine, Adana, Turkey
| | | | - Nurzen Sezgin
- Department of Biochemistiry, Baskent University School of Medicine, Adana, Turkey
| | - Reha N Tandogan
- Department of Orthopedics and Traumatology, Çankaya Hospital, Adana, Turkey
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Jones MH, Spindler KP, Fleming BC, Duryea J, Obuchowski NA, Scaramuzza EA, Oksendahl HL, Winalski CS, Duong CL, Huston LJ, Parker RD, Kaeding CC, Andrish JT, Flanigan DC, Dunn WR, Reinke EK. Meniscus treatment and age associated with narrower radiographic joint space width 2-3 years after ACL reconstruction: data from the MOON onsite cohort. Osteoarthritis Cartilage 2015; 23:581-8. [PMID: 25559582 PMCID: PMC4601556 DOI: 10.1016/j.joca.2014.12.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 12/16/2014] [Accepted: 12/23/2014] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To identify risk factors for radiographic signs of post-traumatic osteoarthritis (OA) 2-3 years after anterior cruciate ligament (ACL) reconstruction through multivariable analysis of minimum joint space width (mJSW) differences in a specially designed nested cohort. METHODS A nested cohort within the Multicenter Orthopaedic Outcomes Network (MOON) cohort included 262 patients (148 females, average age 20) injured in sport who underwent ACL reconstruction in a previously uninjured knee, were 35 or younger, and did not have ACL revision or contralateral knee surgery. mJSW on semi-flexed radiographs was measured in the medial compartment using a validated computerized method. A multivariable generalized linear model was constructed to assess mJSW difference between the ACL reconstructed and contralateral control knees while adjusting for potential confounding factors. RESULTS Unexpectedly, we found the mean mJSW was 0.35 mm wider in ACL reconstructed than in control knees (5.06 mm (95% CI 4.96-5.15 mm) vs 4.71 mm (95% CI 4.62-4.80 mm), P < 0.001). However, ACL reconstructed knees with meniscectomy had narrower mJSW compared to contralateral normal knees by 0.64 mm (95% C.I. 0.38-0.90 mm) (P < 0.001). Age (P < 0.001) and meniscus repair (P = 0.001) were also significantly associated with mJSW difference. CONCLUSION Semi-flexed radiographs can detect differences in mJSW between ACL reconstructed and contralateral normal knees 2-3 years following ACL reconstruction, and the unexpected wider mJSW in ACL reconstructed knees may represent the earliest manifestation of post-traumatic osteoarthritis and warrants further study.
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Affiliation(s)
| | - K P Spindler
- Cleveland Clinic, USA; Vanderbilt University Medical Center, USA.
| | - B C Fleming
- Brown University/Rhode Island Hospital, USA.
| | - J Duryea
- Brigham and Women's Hospital/Harvard Medical School, USA.
| | | | | | | | | | - C L Duong
- Vanderbilt University Medical Center, USA.
| | - L J Huston
- Vanderbilt University Medical Center, USA.
| | | | - C C Kaeding
- The Ohio State University Wexner Medical Center, USA.
| | | | - D C Flanigan
- The Ohio State University Wexner Medical Center, USA.
| | - W R Dunn
- University of Wisconsin School of Medicine and Public Health, USA.
| | - E K Reinke
- Vanderbilt University Medical Center, USA.
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Useful animal models for the research of osteoarthritis. EUROPEAN JOURNAL OF ORTHOPAEDIC SURGERY AND TRAUMATOLOGY 2013; 24:263-71. [PMID: 23508348 DOI: 10.1007/s00590-013-1205-2] [Citation(s) in RCA: 141] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Accepted: 03/01/2013] [Indexed: 12/29/2022]
Abstract
Osteoarthritis (OA) is a major cause of suffering for millions of people. Investigating the disease directly on humans may be challenging. The aim of the present study is to investigate the advantages and limitations of the animal models currently used in OA research. The animal models are divided into induced and spontaneous. Induced models are further subdivided into surgical and chemical models, according to the procedure used to induce OA. Surgical induction of OA is the most commonly used procedure, which alters the exerted strain on the joint and/or alter load bearing leading to instability of the joint and induction of OA. Chemical models are generated by intra-articular injection of modifying factors or by systemically administering noxious agents, such as quinolones. Spontaneous models include naturally occurring and genetic models. Naturally occurring OA is described in certain species, while genetic models are developed by gene manipulation. Overall, there is no single animal model that is ideal for studying degenerative OA. However, in the present review, an attempt is made to clarify the most appropriate use of each model.
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A review of translational animal models for knee osteoarthritis. ARTHRITIS 2012; 2012:764621. [PMID: 23326663 PMCID: PMC3541554 DOI: 10.1155/2012/764621] [Citation(s) in RCA: 156] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 11/08/2012] [Accepted: 11/26/2012] [Indexed: 11/18/2022]
Abstract
Knee osteoarthritis remains a tremendous public health concern, both in terms of health-related quality of life and financial burden of disease. Translational research is a critical step towards understanding and mitigating the long-term effects of this disease process. Animal models provide practical and clinically relevant ways to study both the natural history and response to treatment of knee osteoarthritis. Many factors including size, cost, and method of inducing osteoarthritis are important considerations for choosing an appropriate animal model. Smaller animals are useful because of their ease of use and cost, while larger animals are advantageous because of their anatomical similarity to humans. This evidence-based review will compare and contrast several different animal models for knee osteoarthritis. Our goal is to inform the clinician about current research models, in order to facilitate the transfer of knowledge from the "bench" to the "bedside."
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Hosseini A, Van de Velde S, Gill TJ, Li G. Tibiofemoral cartilage contact biomechanics in patients after reconstruction of a ruptured anterior cruciate ligament. J Orthop Res 2012; 30:1781-8. [PMID: 22528687 PMCID: PMC3407335 DOI: 10.1002/jor.22122] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 03/19/2012] [Indexed: 02/04/2023]
Abstract
We investigated the in vivo cartilage contact biomechanics of the tibiofemoral joint in patients after reconstruction of a ruptured anterior cruciate ligament (ACL). A dual fluoroscopic and MR imaging technique was used to investigate the cartilage contact biomechanics of the tibiofemoral joint during in vivo weight-bearing flexion of the knee in eight patients 6 months following clinically successful reconstruction of an acute isolated ACL rupture. The location of tibiofemoral cartilage contact, size of the contact area, cartilage thickness at the contact area, and magnitude of the cartilage contact deformation of the ACL-reconstructed knees were compared with those previously measured in intact (contralateral) knees and ACL-deficient knees of the same subjects. Contact biomechanics of the tibiofemoral cartilage after ACL reconstruction were similar to those measured in intact knees. However, at lower flexion, the abnormal posterior and lateral shift of cartilage contact location to smaller regions of thinner tibial cartilage that has been described in ACL-deficient knees persisted in ACL-reconstructed knees, resulting in an increase of the magnitude of cartilage contact deformation at those flexion angles. Reconstruction of the ACL restored some of the in vivo cartilage contact biomechanics of the tibiofemoral joint to normal. Clinically, recovering anterior knee stability might be insufficient to prevent post-operative cartilage degeneration due to lack of restoration of in vivo cartilage contact biomechanics.
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Affiliation(s)
- Ali Hosseini
- Bioengineering Laboratory, Massachusetts General Hospital/Harvard Medical School, Boston, MA 02114, USA
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Knights CB, Gentry C, Bevan S. Partial medial meniscectomy produces osteoarthritis pain-related behaviour in female C57BL/6 mice. Pain 2012; 153:281-292. [DOI: 10.1016/j.pain.2011.09.007] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2011] [Revised: 09/08/2011] [Accepted: 09/09/2011] [Indexed: 11/24/2022]
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Stereologic analysis of tibial-plateau cartilage and femoral cancellous bone in guinea pigs with spontaneous osteoarthritis. Clin Orthop Relat Res 2011; 469:2796-805. [PMID: 21516362 PMCID: PMC3171544 DOI: 10.1007/s11999-011-1899-6] [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: 01/31/2023]
Abstract
BACKGROUND Two strains of guinea pig develop spontaneous osteoarthritis of the knee. Although the disease evolves at different rates in the two strains, it is not known whether these differences are reflected in the structure of the cartilage and cancellous bone. QUESTIONS/PURPOSES We determined whether the three-dimensional structure of the tibial-plateau cartilage and femoral cancellous bone differed between the two strains. METHODS Six Dunkin-Hartley and six GOHI/SPF guinea pigs were evaluated. The animals were sacrificed at 11 months of age. The 24 proximal tibias were used for a stereologic histomorphometric analysis of the tibial-plateau cartilage. The 24 femurs were used for a site-specific, three-dimensional quantitative analysis of the cancellous bone by micro-CT. RESULTS Compared to the GOHI/SPF guinea pigs, the tibial-plateau cartilage of the Dunkin-Hartley strain had a larger lesion volume (3.8% versus 1.5%) and a thicker uncalcified cartilage layer (0.042 versus 0.035 mm), but a thinner calcified cartilage zone (0.008 versus 0.01 mm) and a thinner subchondral cortical bone plate (0.035 versus 0.039 mm). The femoral cancellous bone in the Dunkin-Hartley strain had a lower bone mineral density (477 versus 509 mg/cm(3)). However, the trabeculae were thicker (3.91 versus 3.53 pixels) and farther apart (7.8 versus 5.6 pixels). The osteoarthritic changes in the cartilage were topographically mirrored in the subchondral bone. They were most severe on the medial side of the joint, particularly in the anterior region. CONCLUSIONS Spontaneous osteoarthritis in the guinea pig is associated with site-specific changes in the articular cartilage layer, which are topographically mirrored in the underlying subchondral bone. CLINICAL RELEVANCE Three-dimensional structural information not revealed by two-dimensional radiography may help characterize the stages of osteoarthritis.
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Frobell RB. Change in cartilage thickness, posttraumatic bone marrow lesions, and joint fluid volumes after acute ACL disruption: a two-year prospective MRI study of sixty-one subjects. J Bone Joint Surg Am 2011; 93:1096-103. [PMID: 21776546 DOI: 10.2106/jbjs.j.00929] [Citation(s) in RCA: 102] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Little is known about early morphologic change occurring with an acute injury of the anterior cruciate ligament. Magnetic resonance imaging was used in this study to investigate the two-year change in cartilage thickness, bone marrow lesions, and joint fluid of knees with acute anterior cruciate ligament injury treated surgically or nonsurgically and to identify factors associated with these changes. METHODS Sixty-one subjects (sixteen women and forty-five men with a mean age of twenty-six years) with acute anterior cruciate ligament injury to a previously uninjured knee were examined with use of a 1.5-T magnetic resonance imaging scanner at baseline and at three, six, twelve, and twenty-four months after the injury. Thirty-four subjects received rehabilitation and early anterior cruciate ligament reconstruction (a median of 44.5 days after the injury), eleven subjects received rehabilitation and a delayed anterior cruciate ligament reconstruction (408 days), and sixteen received rehabilitation alone. Morphologic measures were obtained from computer-assisted segmentation of magnetic resonance images. Factors tested for association were age, sex, activity level, treatment, and osteochondral fracture at baseline. RESULTS After twenty-four months, significant cartilage thinning occurred in the trochlea of the femur (mean, -4.3%; standard response mean = 0.88), whereas significant cartilage thickening occurred in the central medial aspect of the femur (mean, +2.7%; standard response mean = 0.46). A younger age at the time of injury was a risk factor for thickening in the central medial aspect of femur, whereas older age at injury was a risk factor for thinning in the trochlea of the femur. Treatment of the torn anterior cruciate ligament was not related to these changes nor was activity level or an osteochondral fracture at baseline. Posttraumatic bone marrow lesions in the lateral aspect of the tibia resolved completely in fifty-four of fifty-eight knees (median, six months) and lesions in the lateral aspect of the femur resolved completely in forty-four of forty-seven knees (median, three months); however, thirty new bone marrow lesions developed in the lateral aspect of twenty-one knees over the two-year period. None of the factors were related to the development of bone marrow lesions. CONCLUSIONS Morphologic change as visualized on magnetic resonance imaging occurs in the knee over the first two years after acute anterior cruciate ligament injury as demonstrated by cartilage thickening (central medial aspect of the femur), cartilage thinning (trochlea of the femur), the resolution of posttraumatic bone marrow lesions in the lateral part of the knee, and the development of new bone marrow lesions laterally. Age and male sex were independent risk factors for change in cartilage morphology.
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Affiliation(s)
- Richard B Frobell
- Department of Orthopedics, Clinical Sciences Lund, Lund University, Lund, Sweden.
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Iacob S, Cs-Szabo G. Biglycan regulates the expression of EGF receptors through EGF signaling pathways in human articular chondrocytes. Connect Tissue Res 2010; 51:347-58. [PMID: 20367117 DOI: 10.3109/03008200903427695] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Biglycan is a member of the family of small leucine-rich proteoglycans. It is an important structural component of articular cartilage and participates in the assembly of the chondrocyte extracellular matrix through formation of protein interactions with collagen type VI and large proteoglycan aggregates. Biglycan also possesses signaling properties. In articular chondrocytes, short-term activation of epidermal growth factor receptors (EGFR) with biglycan initiated mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K) signaling events, similar to the effect of epidermal growth factor (EGF) observed in other cell types. The extent and duration of intracellular signaling resolves biological effects initiated by EGFR stimulation, thus, establishing cell fate. In this study, we elucidate a novel regulatory mechanism of EGFR expression in human articular chondrocytes that is modulated by prolonged biglycan treatment and is in contrast to changes detected in the expression of EGFR following EGF stimulation. Treatment of chondrocytes for 24 hr with biglycan upregulated EGFR mRNA and protein expression, whereas treatment with EGF downregulated EGFR message and protein levels. Biglycan and EGF treatment protracted extracellular signal-regulated kinases (ERK1/2) and Akt phosphorylation, albeit to different extents. Mechanistic studies with mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathway-specific inhibitors revealed that biglycan and EGF distinctly modulate the expression of EGFR in chondrocytes. Biglycan promoted the coactivation of ERK1/2 and Akt, however, phosphorylated Akt induced a prolonged inhibition of ERK1/2. Consequently, total EGFR mRNA and protein expression was increased. This regulatory mechanism contrasts the modulation of EGFR expression by exogenous EGF, which strongly protracts ERK1/2 activation, therefore, inducing a decrease of EGFR message and protein levels. Thus, biglycan might impinge on the expression of total EGFR and possibly, on the cell-surface expression of the receptors. These observations suggest that biglycan might play a critical role in the regulation of chondrocyte and pericellular matrix homeostasis.
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Affiliation(s)
- Stanca Iacob
- Department of Biochemistry and Orthopaedic Surgery, Rush University Medical Center, Chicago, Illinois 60612, USA
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Scanlan SF, Chaudhari AMW, Dyrby CO, Andriacchi TP. Differences in tibial rotation during walking in ACL reconstructed and healthy contralateral knees. J Biomech 2010; 43:1817-22. [PMID: 20181339 PMCID: PMC2882513 DOI: 10.1016/j.jbiomech.2010.02.010] [Citation(s) in RCA: 143] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2009] [Revised: 02/05/2010] [Accepted: 02/09/2010] [Indexed: 11/26/2022]
Abstract
This study tested the hypotheses that in patients with a successful anterior cruciate ligament (ACL) reconstruction, the internal-external rotation, varus-valgus, and knee flexion position of reconstructed knees would be different from uninjured contralateral knees during walking. Twenty-six subjects with unilateral ACL reconstructions (avg 31 years, 1.7 m, 68 kg, 15 female, 24 months past reconstruction) and no other history of serious lower limb injury walked at a self-selected speed in the gait laboratory, with the uninjured contralateral knee as a matched control. Kinematic measurements of tibiofemoral motion were made using a previously-described point-cluster technique. Repeated-measures ANOVA (alpha=0.017) was used to compare ACL-reconstructed knees to their contralateral knees at four distinct points during the stance phase of walking. An offset towards external tibial rotation in ACL-reconstructed knees was maintained over all time points (95%CI 2.3+/-1.3 degrees ). Twenty-two out of twenty-six individuals experienced an average external tibial rotation offset throughout stance phase. Varus-valgus rotation and knee flexion were not significantly different between reconstructed and contralateral knees. These findings show that differences in tibial rotation during walking exist in ACL reconstructed knees compared to healthy contralateral knees, providing a potential explanation why these patients are at higher risk of knee osteoarthritis in the long-term.
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Affiliation(s)
- Sean F Scanlan
- Biomechanical Engineering, Department of Mechanical Engineering, Stanford University, Stanford, CA, USA.
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Paul-Murphy JR, Krugner-Higby LA, Tourdot RL, Sladky KK, Klauer JM, Keuler NS, Brown CS, Heath TD. Evaluation of liposome-encapsulated butorphanol tartrate for alleviation of experimentally induced arthritic pain in green-cheeked conures (Pyrrhura molinae). Am J Vet Res 2009; 70:1211-9. [PMID: 19795935 DOI: 10.2460/ajvr.70.10.1211] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To evaluate injection of microcrystalline sodium urate (MSU) for inducing articular pain in green-cheeked conures (Pyrrhura molinae) and the analgesic efficacy of liposome-encapsulated butorphanol tartrate (LEBT) by use of weight load data, behavioral scores, and fecal corticosterone concentration. ANIMALS 8 conures. PROCEDURES In a crossover study, conures were randomly assigned to receive LEBT (15 mg/kg) or liposomal vehicle subsequent to experimental induction of arthritis or sham injection. The MSU was injected into 1 tibiotarsal-tarsometatarsal (intertarsal) joint to induce arthritis (time 0). weight-bearing load and behavioral scores were determined at 0, 2, 6, 26, and 30 hours. RESULTS MSU injection into 1 intertarsal joint caused a temporary decrease in weight bearing on the affected limb. Treatment of arthritic conures with LEBT resulted in significantly more weight bearing on the arthritic limb than treatment with vehicle. Administration of vehicle to arthritic conures caused a decrease in activity and feeding behaviors during the induction phase of arthritis, but as the arthritis resolved, there was a significant increase in voluntary activity at 30 hours and feeding behaviors at 26 and 30 hours, compared with results for LEBT treatment of arthritic birds. Treatment with LEBT or vehicle in conures without arthritis resulted in similar measurements for weight bearing and voluntary and motivated behaviors. CONCLUSIONS AND CLINICAL RELEVANCE Experimental induction of arthritis in conures was a good method for evaluating tonic pain. Weight-bearing load was the most sensitive measure of pain associated with induced arthritis. Pain associated with MSU-induced arthritis was alleviated by administration of LEBT.
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Affiliation(s)
- Joanne R Paul-Murphy
- Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA. paulmurphy@ucdavis
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Paul-Murphy JR, Sladky KK, Krugner-Higby LA, Stading BR, Klauer JM, Keuler NS, Brown CS, Heath TD. Analgesic effects of carprofen and liposome-encapsulated butorphanol tartrate in Hispaniolan parrots (Amazona ventralis) with experimentally induced arthritis. Am J Vet Res 2009; 70:1201-10. [DOI: 10.2460/ajvr.70.10.1201] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Wu Q, Henry JL. Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis. Mol Pain 2009; 5:57. [PMID: 19785765 PMCID: PMC2761878 DOI: 10.1186/1744-8069-5-57] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2009] [Accepted: 09/28/2009] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Clinical data on osteoarthritis (OA) suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naïve control animals. Pilot data indicated no difference in C- or Adelta-fiber associated neurons and therefore the focus is on Abeta-fiber nociceptive neurons. RESULTS At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Abeta-fiber dorsal root ganglion (DRG) neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Abeta-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. CONCLUSION These data indicate that Abeta nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Abeta-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA.
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Affiliation(s)
- Qi Wu
- Michael G DeGroote Institute for Pain Research and Care, McMaster University, 1200 Main Street West, HSC 4N35, Hamilton ON, L8N 3Z5, Canada.
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Chaudhari AMW, Briant PL, Bevill SL, Koo S, Andriacchi TP. Knee kinematics, cartilage morphology, and osteoarthritis after ACL injury. Med Sci Sports Exerc 2008; 40:215-22. [PMID: 18202582 DOI: 10.1249/mss.0b013e31815cbb0e] [Citation(s) in RCA: 277] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This review examines a mechanism for the initiation of osteoarthritis after anterior cruciate ligament (ACL) injury by considering the relationship between reported ambulatory changes after ACL injury, cartilage adaptation to load, and the association between cartilage loads during walking and regional variations in cartilage structure and biology. Taken together, these observations suggest that cartilage degeneration after ACL injury could be caused by a kinematic gait change that shifts ambulatory loading applied to cartilage. Such a shift may cause regions of cartilage to become newly loaded, be subjected to altered levels of compression and tension, or become unloaded. The metabolic sensitivity of chondrocytes to such changes in their mechanical environment, combined with the low adaptation potential of mature cartilage, could lead to cartilage degeneration and premature osteoarthritis after ACL injury. This proposed mechanism demonstrates the value of using the ACL injury model to understand the relationship between mechanics and biology, as well as helping to explain the importance of restoring normal ambulatory kinematics after ACL injury to avoid premature osteoarthritis.
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Affiliation(s)
- Ajit M W Chaudhari
- Department of Orthopaedics, OSU Sports Medicine Center, Ohio State University, 2050 Kenny Road, Columbus, OH 43221, USA.
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Schmerbach KI, Boeltzig CKM, Reif U, Wieser JC, Keller T, Grevel V. In Vitro Comparison of Tibial Plateau Leveling Osteotomy with and Without Use of a Tibial Plateau Leveling Jig. Vet Surg 2007; 36:156-63. [PMID: 17335423 DOI: 10.1111/j.1532-950x.2007.00248.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To evaluate the influence of a tibial plateau leveling jig on osteotomy orientation, fragment reduction, and postoperative tibial plateau angle (TPA) during tibial plateau leveling osteotomy (TPLO). STUDY DESIGN In vitro experimental study. ANIMALS Large-breed canine cadavers (n=20). METHODS TPLO was performed on 40 hindlimbs using 4 methods. Group 1: Jig; dogs in dorsal recumbency with the osteotomy parallel to the distal jig pin. Groups 2-4: No jig; dogs in lateral recumbency with the osteotomy in a vertical orientation (group 2: tibia parallel to the table top; group 3: controlled superimposition of the femoral condyles; group 4: internal rotation of the tibia). Postoperative TPA, fragment reduction, and osteotomy orientation relative to the tibial plateau were compared. Positive or negative values denoted deviation from parallel relative to the tibial plateau. RESULTS Postoperative TPA, fragment reduction, and proximodistal osteotomy orientation were not significantly different between groups. Craniocaudal osteotomy orientation was significantly different (P<.005) from the tibial plateau. Median deviations were -4.0 degrees (group 1), 11.8 degrees (group 2), 11.2 degrees (group 3), and 0.2 degrees (group 4). Group 1 was not significantly different from group 4. CONCLUSIONS A jig is not essential for osteotomy orientation, tibial plateau rotation, or fragment reduction. Comparable results were achieved performing a vertical osteotomy with the tibia slightly internally rotated (10 degrees -15 degrees) and parallel to the table surface. CLINICAL RELEVANCE TPLO without use of a jig reduces surgical trauma, is less time consuming, and reduces cost.
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Affiliation(s)
- Kay Ingo Schmerbach
- Department of Small Animal Medicine, Faculty of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
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Stoker AM, Cook JL, Kuroki K, Fox DB. Site-specific analysis of gene expression in early osteoarthritis using the Pond-Nuki model in dogs. J Orthop Surg Res 2006; 1:8. [PMID: 17150128 PMCID: PMC1636033 DOI: 10.1186/1749-799x-1-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2006] [Accepted: 10/10/2006] [Indexed: 11/10/2022] Open
Abstract
Background Osteoarthritis (OA) is a progressive and debilitating disease that often develops from a focal lesion and may take years to clinically manifest to a complete loss of joint structure and function. Currently, there is not a cure for OA, but early diagnosis and initiation of treatment may dramatically improve the prognosis and quality of life for affected individuals. This study was designed to determine the feasibility of analyzing changes in gene expression of articular cartilage using the Pond-Nuki model two weeks after ACL-transection in dogs, and to characterize the changes observed at this time point. Methods The ACL of four dogs was completely transected arthroscopically, and the contralateral limb was used as the non-operated control. After two weeks the dogs were euthanatized and tissues harvested from the tibial plateau and femoral condyles of both limbs. Two dogs were used for histologic analysis and Mankin scoring. From the other two dogs the surface of the femoral condyle and tibial plateau were divided into four regions each, and tissues were harvested from each region for biochemical (GAG and HP) and gene expression analysis. Significant changes in gene expression were determined using REST-XL, and Mann-Whitney rank sum test was used to analyze biochemical data. Significance was set at (p < 0.05). Results Significant differences were not observed between ACL-X and control limbs for Mankin scores or GAG and HP tissue content. Further, damage to the tissue was not observed grossly by India ink staining. However, significant changes in gene expression were observed between ACL-X and control tissues from each region analyzed, and indicate that a unique regional gene expression profile for impending ACL-X induced joint pathology may be identified in future studies. Conclusion The data obtained from this study lend credence to the research approach and model for the characterization of OA, and the identification and validation of future diagnostic modalities. Further, the changes observed in this study may reflect the earliest changes in AC reported during the development of OA, and may signify pathologic changes within a stage of disease that is potentially reversible.
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Affiliation(s)
- Aaron M Stoker
- The Comparative Orthopaedic Laboratory, University of Missouri Columbia, 379 E Campus Dr, Columbia, MO, USA
| | - James L Cook
- The Comparative Orthopaedic Laboratory, University of Missouri Columbia, 379 E Campus Dr, Columbia, MO, USA
| | - Keiichi Kuroki
- Kansas State University Veterinary Diagnostic Laboratory, Kansas State University, 1800 Denison Avenue, Manhattan, KS, USA
| | - Derek B Fox
- The Comparative Orthopaedic Laboratory, University of Missouri Columbia, 379 E Campus Dr, Columbia, MO, USA
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Wadhwa S, Embree MC, Kilts T, Young MF, Ameye LG. Accelerated osteoarthritis in the temporomandibular joint of biglycan/fibromodulin double-deficient mice. Osteoarthritis Cartilage 2005; 13:817-27. [PMID: 16006154 DOI: 10.1016/j.joca.2005.04.016] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2004] [Accepted: 04/18/2005] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To investigate whether the absence of biglycan and fibromodulin, two proteoglycans expressed in cartilage, bone and tendon, resulted in accelerated osteoarthritis in the temporomandibular joint (TMJ). METHODS Histological sections of TMJ from 3-, 6-, 9- and 18-month-old wild-type (WT) and biglycan/fibromodulin double-deficient (DKO) mice were compared. Immuno-stainings for biglycan, fibromodulin and proliferating cell nuclear antigen (PCNA) were performed. RESULTS Biglycan and fibromodulin were highly expressed in the disc and articular cartilage of the TMJ. At 3 months of age, both WT and DKO presented early signs of cartilage degeneration visible as small acellular areas under the articular surfaces and superficial waving. From 6 months of age, DKOs developed accelerated osteoarthritis compared to WT. At 6 months, small vertical clefts in the condylar cartilage and partial disruption of the disk were visible in the DKO. In addition, chondrocytes had lost their regular columnar organization to form clusters. At 9 months, these differences were even more pronounced. At 18 months, extended cartilage erosion was visible in DKOs when by comparison the thickness of the articular cartilage in WT controls was basically intact. PCNA staining was stronger in 3-month-old WT TMJ fibrocartilage than in 3-month-old DKO TMJ fibrocartilage suggesting that chondrocyte proliferation might be impaired in DKOs. CONCLUSION The biglycan/fibromodulin double knock-out mouse constitutes a useful animal model to decipher the pathobiology of osteoarthritis in the TMJ.
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Affiliation(s)
- S Wadhwa
- Molecular Biology of Bones and Teeth Unit, Craniofacial and Skeletal Diseases Branch, NIDCR, NIH, DHHS Bethesda, MD 20892, USA
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Hofstaetter JG, Wunderlich L, Samuel RE, Saad FA, Choi YH, Glimcher MJ. Systemic hypoxia alters gene expression levels of structural proteins and growth factors in knee joint cartilage. Biochem Biophys Res Commun 2005; 330:386-94. [PMID: 15796895 DOI: 10.1016/j.bbrc.2005.02.168] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2005] [Indexed: 10/25/2022]
Abstract
We investigated the effects of short- (8- and 24-h) and long-term (3 weeks) exposure to systemic normobaric hypoxia (13%) on the gene expression level of structural proteins and growth factors in knee joint cartilage of rabbits. Collagen type Ia2, II, and Va1, TGF-beta1, and b-FGF were upregulated after short-term hypoxia in both menisci, but not in articular cartilage. In contrast, long-term hypoxia downregulated gene expression level of collagens, aggrecan, and growth factors in articular cartilage and meniscal fibrocartilage. Interestingly, gene expression levels of non-collagenous proteins biglycan, decorin, and versican were not affected by short-term or by long-term hypoxia in knee joint cartilage. The present study suggests that changes in oxygen level differentially affect gene expression levels of growth factors, collagens, and non-collagenous proteins in normal knee joint cartilage in rabbits.
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Affiliation(s)
- Jochen G Hofstaetter
- Laboratory for Skeletal Disorders and Rehabilitation, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02215, USA.
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Young AA, Smith MM, Smith SM, Cake MA, Ghosh P, Read RA, Melrose J, Sonnabend DH, Roughley PJ, Little CB. Regional assessment of articular cartilage gene expression and small proteoglycan metabolism in an animal model of osteoarthritis. Arthritis Res Ther 2005; 7:R852-61. [PMID: 15987487 PMCID: PMC1175037 DOI: 10.1186/ar1756] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2005] [Revised: 04/09/2005] [Accepted: 04/14/2005] [Indexed: 12/01/2022] Open
Abstract
Osteoarthritis (OA), the commonest form of arthritis and a major cause of morbidity, is characterized by progressive degeneration of the articular cartilage. Along with increased production and activation of degradative enzymes, altered synthesis of cartilage matrix molecules and growth factors by resident chondrocytes is believed to play a central role in this pathological process. We used an ovine meniscectomy model of OA to evaluate changes in chondrocyte expression of types I, II and III collagen; aggrecan; the small leucine-rich proteoglycans (SLRPs) biglycan, decorin, lumican and fibromodulin; transforming growth factor-β; and connective tissue growth factor. Changes were evaluated separately in the medial and lateral tibial plateaux, and were confirmed for selected molecules using immunohistochemistry and Western blotting. Significant changes in mRNA levels were confined to the lateral compartment, where active cartilage degeneration was observed. In this region there was significant upregulation in expession of types I, II and III collagen, aggrecan, biglycan and lumican, concomitant with downregulation of decorin and connective tissue growth factor. The increases in type I and III collagen mRNA were accompanied by increased immunostaining for these proteins in cartilage. The upregulated lumican expression in degenerative cartilage was associated with increased lumican core protein deficient in keratan sulphate side-chains. Furthermore, there was evidence of significant fragmentation of SLRPs in both normal and arthritic tissue, with specific catabolites of biglycan and fibromodulin identified only in the cartilage from meniscectomized joints. This study highlights the focal nature of the degenerative changes that occur in OA cartilage and suggests that altered synthesis and proteolysis of SLRPs may play an important role in cartilage destruction in arthritis.
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Affiliation(s)
- Allan A Young
- Raymond Purves Research Laboratory, Institute of Bone and Joint Research, Royal North Shore Hospital, University of Sydney, St Leonards, New South Wales, Australia.
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