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      WNT16 antagonises excessive canonical WNT activation and protects cartilage in osteoarthritis

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          Abstract

          Objective

          Both excessive and insufficient activation of WNT signalling results in cartilage breakdown and osteoarthritis. WNT16 is upregulated in the articular cartilage following injury and in osteoarthritis. Here, we investigate the function of WNT16 in osteoarthritis and the downstream molecular mechanisms.

          Methods

          Osteoarthritis was induced by destabilisation of the medial meniscus in wild-type and WNT16-deficient mice. Molecular mechanisms and downstream effects were studied in vitro and in vivo in primary cartilage progenitor cells and primary chondrocytes. The pathway downstream of WNT16 was studied in primary chondrocytes and using the axis duplication assay in Xenopus.

          Results

          WNT16-deficient mice developed more severe osteoarthritis with reduced expression of lubricin and increased chondrocyte apoptosis. WNT16 supported the phenotype of cartilage superficial-zone progenitor cells and lubricin expression. Increased osteoarthritis in WNT16-deficient mice was associated with excessive activation of canonical WNT signalling. In vitro, high doses of WNT16 weakly activated canonical WNT signalling, but, in co-stimulation experiments, WNT16 reduced the capacity of WNT3a to activate the canonical WNT pathway. In vivo, WNT16 rescued the WNT8-induced primary axis duplication in Xenopus embryos.

          Conclusions

          In osteoarthritis, WNT16 maintains a balanced canonical WNT signalling and prevents detrimental excessive activation, thereby supporting the homeostasis of progenitor cells.

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          The bone-cartilage unit in osteoarthritis.

          Rik Lories, Frank Luyten (2011)
          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.
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            Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice.

            Mei Feng Zhu, Dezhi Tang, Qiuqian Wu … (2009)
            Osteoarthritis (OA) is a degenerative joint disease, and the mechanism of its pathogenesis is poorly understood. Recent human genetic association studies showed that mutations in the Frzb gene predispose patients to OA, suggesting that the Wnt/beta-catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for beta-catenin in this disease has not been reported. Because tissue-specific activation of the beta-catenin gene (targeted by Col2a1-Cre) is embryonic lethal, we specifically activated the beta-catenin gene in articular chondrocytes in adult mice by generating beta-catenin conditional activation (cAct) mice through breeding of beta-catenin(fx(Ex3)/fx(Ex3)) mice with Col2a1-CreER(T2) transgenic mice. Deletion of exon 3 of the beta-catenin gene results in the production of a stabilized fusion beta-catenin protein that is resistant to phosphorylation by GSK-3beta. In this study, tamoxifen was administered to the 3- and 6-mo-old Col2a1-CreER(T2);beta-catenin(fx(Ex3)/wt) mice, and tissues were harvested for histologic analysis 2 mo after tamoxifen induction. Overexpression of beta-catenin protein was detected by immunostaining in articular cartilage tissues of beta-catenin cAct mice. In 5-mo-old beta-catenin cAct mice, reduction of Safranin O and Alcian blue staining in articular cartilage tissue and reduced articular cartilage area were observed. In 8-mo-old beta-catenin cAct mice, cell cloning, surface fibrillation, vertical clefting, and chondrophyte/osteophyte formation were observed. Complete loss of articular cartilage layers and the formation of new woven bone in the subchondral bone area were also found in beta-catenin cAct mice. Expression of chondrocyte marker genes, such as aggrecan, Mmp-9, Mmp-13, Alp, Oc, and colX, was significantly increased (3- to 6-fold) in articular chondrocytes derived from beta-catenin cAct mice. Bmp2 but not Bmp4 expression was also significantly upregulated (6-fold increase) in these cells. In addition, we also observed overexpression of beta-catenin protein in the knee joint samples from patients with OA. These findings indicate that activation of beta-catenin signaling in articular chondrocytes in adult mice leads to the premature chondrocyte differentiation and the development of an OA-like phenotype. This study provides direct and definitive evidence about the role of beta-catenin in the development of OA.
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              Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.

              Sofia Movérare-Skrtic, Petra Henning, XIANWEN LIU … (2014)
              The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Rheum Dis
                Journal ID (iso-abbrev): Ann. Rheum. Dis
                Journal ID (hwp): annrheumdis
                Journal ID (publisher-id): ard
                Title: Annals of the Rheumatic Diseases
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Print): 0003-4967
                ISSN (Electronic): 1468-2060
                Publication date (Print): January 2017
                Publication date (Electronic): 04 May 2016
                Volume: 76
                Issue: 1
                Pages: 218-226
                Affiliations
                [1 ]Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London , London, UK
                [2 ]Institute of Experimental Musculoskeletal Medicine, University Hospital Muenster , Muenster, Germany
                [3 ]Department of Cell Biology, The Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia School of Medicine , Charlottesville, Virginia, USA
                [4 ]Department of Medicine & Rheumatology Unit, Rizzoli Orthopaedic Institute , Bologna, Italy
                [5 ]Department of Biomedical & Neuromotor Sciences, University of Bologna , Bologna, Italy
                [6 ]Department of Cell and Developmental Biology, University College London , London, UK
                [7 ]Department of Internal Medicine 3, Institute of Clinical Immunology, Friedrich-Alexander-University Erlangen-Nuremberg , Erlangen, Germany
                [8 ]Centre for Integrative Physiology, School of Biomedical Sciences, University of Edinburgh , Edinburgh, UK
                Author notes

                Handling editor Tore K Kvien

                [Correspondence to ] Dr Bethan Lynne Thomas, Barts and the London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK; b.l.thomas@ 123456qmul.ac.uk

                GN and BLT contributed equally to this manuscript and are co-first authors.

                Article
                Publisher ID: annrheumdis-2015-208577
                DOI: 10.1136/annrheumdis-2015-208577
                PMC ID: 5264226
                PubMed ID: 27147711
                SO-VID: 30babf9f-ffe9-411d-925f-90cb3a4417d1
                Copyright © Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
                License:

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                Date received : 24 September 2015
                Date revision received : 21 March 2016
                Date accepted : 23 March 2016
                Categories
                Subject: 1506
                Subject: Basic and Translational Research
                Series title: Extended report
                Custom metadata
                special-feature unlocked

                ScienceOpen disciplines: Immunology
                Keywords: chondrocytes,knee osteoarthritis,osteoarthritis
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: chondrocytes, knee osteoarthritis, osteoarthritis

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