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      Full-thickness cartilage defects are repaired via a microfracture technique and intraarticular injection of the small-molecule compound kartogenin

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          Abstract

          Introduction

          Microfracture does not properly repair full-thickness cartilage defects. The purpose of this study was to evaluate the effect of intraarticular injection of the small-molecule compound kartogenin (KGN) on the restoration of a full-thickness cartilage defect treated with microfracture in a rabbit model.

          Methods

          Full-thickness cartilage defects (3.5 mm in diameter and 3 mm in depth) were created in the patellar groove of the right femurs of 24 female New Zealand White rabbits. The rabbits were divided into two groups (12 in each group) based on postsurgery treatment differences, as follows: microfracture plus weekly intraarticular injection of KGN (group 1) and microfracture plus dimethyl sulfoxide (group 2). Six rabbits from each group were illed at 4 and 12 weeks after surgery, and their knees were harvested. The outcome was assessed both macroscopically, by using the International Cartilage Repair Society (ICRS) macroscopic evaluation system, and histologically, by using the modified O’Driscoll histologic scoring system. Immunohistochemistry for type II and I collagen was also conducted.

          Results

          At 4 weeks, group 1 showed better defect filling and a greater number of chondrocyte-like cells compared with group 2. At 12 weeks, group 1 showed statistically significantly higher ICRS scores and modified O’Driscoll scores compared with group 2. More hyaline cartilage-like tissue was found in the defects of group 1 at 12 weeks.

          Conclusions

          Intraarticular injection of KGN enhances the quality of full-thickness cartilage defects repair after microfracture, with better defect filling and increased hyaline-like cartilage formation.

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          Most cited references26

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          A stem cell-based approach to cartilage repair.

          Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.
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            Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study.

            A common approach for tissue regeneration is cell delivery, for example by direct transplantation of stem or progenitor cells. An alternative, by recruitment of endogenous cells, needs experimental evidence. We tested the hypothesis that the articular surface of the synovial joint can regenerate with a biological cue spatially embedded in an anatomically correct bioscaffold. In this proof of concept study, the surface morphology of a rabbit proximal humeral joint was captured with laser scanning and reconstructed by computer-aided design. We fabricated an anatomically correct bioscaffold using a composite of poly-epsilon-caprolactone and hydroxyapatite. The entire articular surface of unilateral proximal humeral condyles of skeletally mature rabbits was surgically excised and replaced with bioscaffolds spatially infused with transforming growth factor beta3 (TGFbeta3)-adsorbed or TGFbeta3-free collagen hydrogel. Locomotion and weightbearing were assessed 1-2, 3-4, and 5-8 weeks after surgery. At 4 months, regenerated cartilage samples were retrieved from in vivo and assessed for surface fissure, thickness, density, chondrocyte numbers, collagen type II and aggrecan, and mechanical properties. Ten rabbits received TGFbeta3-infused bioscaffolds, ten received TGFbeta3-free bioscaffolds, and three rabbits underwent humeral-head excision without bioscaffold replacement. All animals in the TGFbeta3-delivery group fully resumed weightbearing and locomotion 3-4 weeks after surgery, more consistently than those in the TGFbeta3-free group. Defect-only rabbits limped at all times. 4 months after surgery, TGFbeta3-infused bioscaffolds were fully covered with hyaline cartilage in the articular surface. TGFbeta3-free bioscaffolds had only isolated cartilage formation, and no cartilage formation occurred in defect-only rabbits. TGFbeta3 delivery yielded uniformly distributed chondrocytes in a matrix with collagen type II and aggrecan and had significantly greater thickness (p=0.044) and density (p<0.0001) than did cartilage formed without TGFbeta3. Compressive and shear properties of TGFbeta3-mediated articular cartilage did not differ from those of native articular cartilage, and were significantly greater than those of cartilage formed without TGFbeta3. Regenerated cartilage was avascular and integrated with regenerated subchondral bone that had well defined blood vessels. TGFbeta3 delivery recruited roughly 130% more cells in the regenerated articular cartilage than did spontaneous cell migration without TGFbeta3. Our findings suggest that the entire articular surface of the synovial joint can regenerate without cell transplantation. Regeneration of complex tissues is probable by homing of endogenous cells, as exemplified by stratified avascular cartilage and vascularised bone. Whether cell homing acts as an adjunctive or alternative approach of cell delivery for regeneration of tissues with different organisational complexity warrants further investigation. New York State Stem Cell Science; US National Institutes of Health. Copyright 2010 Elsevier Ltd. All rights reserved.
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              Results after microfracture of full-thickness chondral defects in different compartments in the knee.

              To determine if the clinical results after microfracture of full-thickness cartilage lesions deteriorate over a period of 36 months. Between 1999 and 2002 85 patients (mean age 39.5 years) with full-thickness cartilage lesions underwent the microfracture procedure and were evaluated preoperatively and 6, 18 and 36 months after surgery. Exclusion criteria were meniscal pathologies, axial malpositioning and ligament instabilities. Baseline clinical scores were compared with follow-up data by paired Wilcoxon-tests for the modified Cincinnati knee and the International Cartilage Repair Society (ICRS)-score. The effects of the lesion localization and Magnetic resonance imaging (MRI) parameters were evaluated using the Pearson correlation and independent samples tests. Both scores revealed significant improvement 18 months after microfracture (P<0.0001). Within the second 18 months after surgery there was a significant deterioration in the ICRS-score (P<0.0001). The best results could be observed in chondral lesions of the femoral condyles. Defects in other areas of the knee deteriorated between 18 and 36 months after microfracture. MRI 36 months after surgery revealed best defect filling in lesions on the femoral condyles with significant difference in the other areas (P<0.02). The Pearson coefficient of correlation between defect filling and ICRS-score was 0.84 and significant at the 0.01 level. Microfracture is a minimal invasive method with good short-term results in the treatment of small cartilage defects. A deterioration of the results starts 18 months after surgery and is most evident in the ICRS-score. The best prognostic factors have young patients with defects on the femoral condyles.
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                Author and article information

                Contributors
                xuxingquan12345@163.com
                shidongquan1215@163.com
                shenyeshuaisys@163.com
                xuzhihongjoint@hotmail.com
                daijin.nju@gmail.com
                amoysun@hotmail.com
                tenghj@hotmail.com
                qingj@nju.edu.cn
                Journal
                Arthritis Res Ther
                Arthritis Research & Therapy
                BioMed Central (London )
                1478-6354
                1478-6362
                2 February 2015
                2 February 2015
                2015
                : 17
                : 1
                : 20
                Affiliations
                [ ]The Center of Diagnosis and Treatment for Joint Disease, Drum Tower Hospital, Medical School, Nanjing University, Zhongshan Road 321, Nanjing, 210008 Jiangsu China
                [ ]Joint Research Center for Bone and Joint Disease, Model Animal Research Center (MARC), Nanjing University, Nanjing, 210093 Jiangsu China
                Article
                537
                10.1186/s13075-015-0537-1
                4376363
                25641548
                02b65094-c89b-4c7a-be9f-3d6c9f6dd987
                © Xu et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 August 2014
                : 22 January 2015
                Categories
                Research Article
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                © The Author(s) 2015

                Orthopedics
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