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      Prematurely aging mitochondrial DNA mutator mice display subchondral osteopenia and chondrocyte hypertrophy without further osteoarthritis features

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          Abstract

          Mitochondrial mutations and dysfunction have been demonstrated in several age-related disorders including osteoarthritis, yet its relative contribution to pathogenesis remains unknown. Here we evaluated whether premature aging caused by accumulation of mitochondrial DNA mutations in Polg D2 75A mice predisposes to the development of knee osteoarthritis. Compared with wild type animals, homozygous Polg D275A mice displayed a specific bone phenotype characterized by osteopenia of epiphyseal trabecular bone and subchondral cortical plate. Trabecular thickness was significantly associated with osteocyte apoptosis rates and osteoclasts numbers were increased in subchondral bone tissues. While chondrocyte apoptosis rates in articular and growth plate cartilage were similar between groups, homozygous mitochondrial DNA mutator mice displayed elevated numbers of hypertrophic chondrocytes in articular calcified cartilage. Low grade cartilage degeneration, predominantly loss of proteoglycans, was present in all genotypes and the development of osteoarthritis features was not found accelerated in premature aging. Somatically acquired mitochondrial DNA mutations predispose to elevated subchondral bone turnover and hypertrophy in calcified cartilage, yet additional mechanical or metabolic stimuli would seem required for induction and accelerated progression of aging-associated osteoarthritis.

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          Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes.

          Mitochondrial dysfunction, oxidative stress and chondrocyte death are important contributors to the development and pathogenesis of osteoarthritis (OA). In this study, we determined the expression and role of Parkin in the clearance of damaged/dysfunctional mitochondria, regulation of reactive oxygen species (ROS) levels and chondrocyte survival under pathological conditions.
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            In early OA, thinning of the subchondral plate is directly related to cartilage damage: results from a canine ACLT-meniscectomy model.

            The pathogenesis of osteoarthritis (OA) includes cartilage degeneration, synovial inflammation, and bone changes. Slowly, the sequence and inter-relationship of these features is becoming clearer. Early models of OA suggest thinning of the subchondral plate in addition to trabecular bone changes. In the present study subchondral bone changes were studied in the canine anterior cruciate ligament transection (ACLT)-meniscectomy model. This model is characterized by intra-joint variability with respect to cartilage damage (predominantly medial) and loading (lateral unloading due to a shifted axis). In 13 Labrador dogs, OA was induced by transection of the anterior cruciate ligament and removal of the medial meniscus. Twelve weeks later, cartilage integrity was evaluated histologically using the modified Mankin score (0-11), and proteoglycan content was determined by Alcian Blue assay. Bone architecture of the tibia was quantified by micro-CT. Cartilage damage was severe in the medial compartment (Mankin score +3.5, glycosaminoglycan (GAG) content -28%) and mild in the lateral compartment (Mankin score +1.6, GAG content -15%). Thinning and porosity of the subchondral plate were only present on the medial side (-21%, +87%, respectively). Interestingly, changes in trabecular bone structure did almost not occur in the medial compartment (volume fraction -7%) but were clear in the lateral compartment (-20%). Thinning of the subchondral plate is a localized phenomenon related to cartilage degeneration while trabecular bone changes are related to mechanical (un)loading. The different mechanisms responsible for bone changes in OA should be taken in account when designing and interpreting studies interfering with bone turnover in the treatment of OA. Copyright 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
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              Bone histomorphometry using free and commonly available software.

              Histomorphometric analysis is a widely used technique to assess changes in tissue structure and function. Commercially available programs that measure histomorphometric parameters can be cost-prohibitive. In this study, we compared an inexpensive method of histomorphometry to a current proprietary software program.
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                Author and article information

                Contributors
                thomas.hugle@chuv.ch
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                28 January 2020
                28 January 2020
                2020
                : 10
                : 1296
                Affiliations
                [1 ]ISNI 0000 0001 0423 4662, GRID grid.8515.9, Department of Rheumatology, , Lausanne University Hospital (CHUV), ; Lausanne, Switzerland
                [2 ]GRID grid.410567.1, Department of Biomedical Engineering, , University Hospital of Basel, ; Basel, Switzerland
                [3 ]ISNI 0000 0004 1937 0642, GRID grid.6612.3, Department of Anatomy, , University of Basel, ; Basel, Switzerland
                [4 ]ISNI 0000 0001 0701 8607, GRID grid.28803.31, Departments of Genetics and Medical Genetics, , University of Wisconsin, ; Madison, USA
                [5 ]GRID grid.410567.1, Department of Rheumatology, , University Hospital of Basel, ; Basel, Switzerland
                Author information
                http://orcid.org/0000-0002-4367-4641
                Article
                58385
                10.1038/s41598-020-58385-w
                6987232
                31992827
                d3d81c4f-4e3e-4f93-be71-0d31603663b6
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 May 2019
                : 15 January 2020
                Categories
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                Custom metadata
                © The Author(s) 2020

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                dna damage and repair,bone
                Uncategorized
                dna damage and repair, bone

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