113
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Targets, models and challenges in osteoarthritis research

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Osteoarthritis is a chronic degenerative disorder of the joint and represents one of the most common diseases worldwide. Its prevalence and severity are increasing owing to aging of the population, but treatment options remain largely limited to painkillers and anti-inflammatory drugs, which only provide symptomatic relief. In the late stages of the disease, surgical interventions are often necessary to partially restore joint function. Although the focus of osteoarthritis research has been originally on the articular cartilage, novel findings are now pointing to osteoarthritis as a disease of the whole joint, in which failure of different joint components can occur. In this Review, we summarize recent progress in the field, including data from novel ‘omics’ technologies and from a number of preclinical and clinical trials. We describe different in vitro and in vivo systems that can be used to study molecules, pathways and cells that are involved in osteoarthritis. We illustrate that a comprehensive and multisystem approach is necessary to understand the complexity and heterogeneity of the disease and to better guide the development of novel therapeutic strategies for osteoarthritis.

          Related collections

          Most cited references155

          • Record: found
          • Abstract: found
          • Article: not found

          Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor.

          Mislocated enzymatic activity of DOT1L has been proposed as a driver of leukemogenesis in mixed lineage leukemia (MLL). The characterization of EPZ004777, a potent, selective inhibitor of DOT1L is reported. Treatment of MLL cells with the compound selectively inhibits H3K79 methylation and blocks expression of leukemogenic genes. Exposure of leukemic cells to EPZ004777 results in selective killing of those cells bearing the MLL gene translocation, with little effect on non-MLL-translocated cells. Finally, in vivo administration of EPZ004777 leads to extension of survival in a mouse MLL xenograft model. These results provide compelling support for DOT1L inhibition as a basis for targeted therapeutics against MLL. Copyright © 2011 Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            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.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The bone-cartilage unit in osteoarthritis.

              Osteoarthritis (OA) refers to a group of mechanically-induced joint disorders to which both genetic and acquired factors contribute. Current pathophysiological concepts focus on OA as a disease of the whole joint. Within these models, the functional unit formed by the articular cartilage and the subchondral bone seems to be of particular interest. Cartilage and bone receive and dissipate the stress associated with movement and loading, and are therefore continuously challenged biomechanically. Recent data support the view that cartilage and bone can communicate over the calcified tissue barrier; vessels reach out from bone into the cartilage zone, patches of uncalcified cartilage are in contact with bone, and microcracks and fissures further facilitate transfer of molecules. Several molecular signaling pathways such as bone morphogenetic proteins and Wnts are hypothesized to have a role in OA and can activate cellular and molecular processes in both cartilage and bone cells. In addition, intracellular activation of different kinase cascades seems to be involved in the molecular crosstalk between cartilage and bone cells. Further research is required to integrate these different elements into a comprehensive approach that will increase our understanding of the disease processes in OA, and that could lead to the development of specific therapeutics or treatment strategies.
                Bookmark

                Author and article information

                Journal
                Dis Model Mech
                Dis Model Mech
                dmm
                DMM
                Disease Models & Mechanisms
                The Company of Biologists Limited
                1754-8403
                1754-8411
                January 2015
                : 8
                : 1
                : 17-30
                Affiliations
                [1 ]Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, 3000 Leuven, Belgium.
                [2 ]Skeletal Biology and Engineering Research Center, KU Leuven, 3000 Leuven, Belgium.
                [3 ]Division of Rheumatology, University Hospitals Leuven, KU Leuven, 3000 Leuven, Belgium.
                Author notes
                [* ]Author for correspondence ( Rik.Lories@ 123456uz.kuleuven.be )
                Article
                0080017
                10.1242/dmm.016881
                4283647
                25561745
                59a39009-5589-42e5-93bb-8b5241569f2d
                © 2015. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                Categories
                Review

                Molecular medicine
                osteoarthritis,cartilage,bone,animal models
                Molecular medicine
                osteoarthritis, cartilage, bone, animal models

                Comments

                Comment on this article