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      24R,25-Dihydroxyvitamin D3 Protects against Articular Cartilage Damage following Anterior Cruciate Ligament Transection in Male Rats

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          Abstract

          Osteoarthritis (OA) in humans is associated with low circulating 25-hydroxyvitamin D3 [25(OH)D 3]. In vitamin D replete rats, radiolabeled 24R,25-dihydroxyvitamin D3 [24R,25(OH) 2D 3] accumulates in articular cartilage following injection of [ 3H]-25(OH)D 3. Previously, we showed that 24R,25(OH) 2D 3 blocks chondrocyte apoptosis via phospholipase D and p53, suggesting a role for 24R,25(OH) 2D 3 in maintaining cartilage health. We examined the ability of 24R,25(OH) 2D 3 to prevent degenerative changes in articular cartilage in an OA-like environment and the potential mechanisms involved. In vitro, rat articular chondrocytes were treated with IL-1β with and without 24R,25(OH) 2D 3 or 1α,25(OH) 2D 3. 24R,25(OH) 2D 3 but not 1α,25(OH) 2D 3 blocked the effects of IL-1β in a dose-dependent manner, and its effect was partially mediated through the TGF-β1 signaling pathway. In vivo, unilateral anterior cruciate ligament transections were performed in immunocompetent rats followed by intra-articular injections of 24R,25(OH) 2D 3 or vehicle (t = 0, 7, 14, 21 days). Tissues were harvested on day 28. Joints treated with vehicle had changes typical of OA whereas joints treated with 24R,25(OH) 2D 3 had less articular cartilage damage and levels of inflammatory mediators. These results indicate that 24R,25(OH) 2D 3 protects against OA, and suggest that it may be a therapeutic approach for preventing trauma-induced osteoarthritis.

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          Most cited references62

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          Osteoarthritis cartilage histopathology: grading and staging.

          Current osteoarthritis (OA) histopathology assessment methods have difficulties in their utility for early disease, as well as their reproducibility and validity. Our objective was to devise a more useful method to assess OA histopathology that would have wide application for clinical and experimental OA assessment and would become recognized as the standard method. An OARSI Working Group deliberated on principles, standards and features for an OA cartilage pathology assessment system. Using current knowledge of the pathophysiology of OA morphologic features, a proposed system was presented at OARSI 2000. Subsequently, this was widely circulated for comments amongst experts in OA pathology. An OA cartilage pathology assessment system based on six grades, which reflect depth of the lesion and four stages reflecting extent of OA over the joint surface was developed. The OARSI cartilage OA histopathology grading system appears consistent and simple to apply. Further studies are required to confirm the system's utility.
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            The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the rat.

            During the development of disease-modifying osteoarthritis (OA) drugs, rat models of OA are frequently used for a first assessment of in vivo efficacy. The most efficacious compound in the rat model may then be tested in a larger animal model before entering human trials. The aim of this study was to describe a histologic scoring system for use in different models of OA in rats that allows standardization and comparison of results obtained by different investigators. The experience of the authors with current scoring systems and the range of lesions observed in rat and human OA studies were considered in recommending this common paradigm for rat histologic scoring. Considerations were made for reproducibility and ease of use for new scorers. Additional scoring paradigms may be employed to further identify specific effects of some disease-modifying drugs. Although the described scoring system is more complex than the modified Mankin scores, which are recommended for some other species, the reliability study showed that it is easily understood and can be reproducibly used, even by inexperienced scorers. The scoring paradigm described here has been found to be sufficiently sensitive to discriminate between treatments and to have high reproducibility. Therefore we recommend its use for evaluation of different rat OA models as well as assessment of disease-modifying effects of treatments in these models. Copyright © 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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              Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction.

              Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                30 August 2016
                2016
                : 11
                : 8
                : e0161782
                Affiliations
                [1 ]Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, Virginia, United States of America
                [2 ]Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University, College of Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
                [3 ]School of Mechanical Engineering, College of Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America
                [4 ]Department of Orthopedic Surgery, University of California San Diego, San Diego, California, United States of America
                [5 ]Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
                Ohio State University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: ZS BDB.

                • Data curation: SLH.

                • Formal analysis: ZS BDB RDC.

                • Funding acquisition: BDB RDC.

                • Investigation: QP KMS RH.

                • Methodology: RH RDC ZS SLH QP.

                • Project administration: ZS SLH.

                • Resources: BDB ZS.

                • Supervision: ZS BDB.

                • Validation: KMS.

                • Visualization: SLH.

                • Writing – original draft: QP.

                • Writing – review & editing: ZS SLH BDB.

                Article
                PONE-D-16-19966
                10.1371/journal.pone.0161782
                5019362
                27575371
                eea9f761-49fe-4be7-89d9-2a9911458af0
                © 2016 Boyan et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 17 May 2016
                : 11 August 2016
                Page count
                Figures: 9, Tables: 1, Pages: 23
                Funding
                Funded by: Society of Womens Health Research
                Award Recipient :
                Funded by: Price Gilbert Jr. Foundation
                Award Recipient :
                This research was supported by grants from the Society for Women’s Health Research [ http://www.womenshealthresearch.org/] and the Price Gilbert Jr. Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Cartilage
                Chondrocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Cartilage
                Chondrocytes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Connective Tissue Cells
                Chondrocytes
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Chondrocytes
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Connective Tissue Cells
                Chondrocytes
                Medicine and Health Sciences
                Rheumatology
                Arthritis
                Osteoarthritis
                Biology and life sciences
                Cell biology
                Signal transduction
                Cell signaling
                Signaling cascades
                TGF-beta signaling cascade
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Limbs (Anatomy)
                Legs
                Knees
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Limbs (Anatomy)
                Legs
                Knees
                Biology and Life Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Cartilage
                Articular Cartilage
                Medicine and Health Sciences
                Anatomy
                Biological Tissue
                Connective Tissue
                Cartilage
                Articular Cartilage
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
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                Medicine and Health Sciences
                Physiology
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                Synovial Fluid
                Biology and Life Sciences
                Anatomy
                Musculoskeletal System
                Joints (Anatomy)
                Knee Joints
                Medicine and Health Sciences
                Anatomy
                Musculoskeletal System
                Joints (Anatomy)
                Knee Joints
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                All relevant data are within the paper and its Supporting Information files.

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