Activation of β-Catenin Signaling in Articular Chondrocytes Leads to Osteoarthritis-Like Phenotype in Adult β-Catenin Conditional Activation Mice

Authors

  • Mei Zhu,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Dezhi Tang,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
    2. Spine Research Institute, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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  • Qiuqian Wu,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Suyang Hao,

    1. Department of Pathology, UMass Memorial Medical Center, University of Massachusetts, Worcester, Massachusetts, USA
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  • Mo Chen,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Chao Xie,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Randy N Rosier,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Regis J O'Keefe,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Michael Zuscik,

    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
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  • Di Chen

    Corresponding author
    1. Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester School of Medicine, Rochester, New York, USA
    • Address reprint requests to: Di Chen, MD, PhD, Department of Orthopaedics, University of Rochester, 601 Elmwood Avenue, Box 665, Rochester, NY 14642, USA
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  • The authors state that they have no conflicts of interest.

Abstract

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/β-catenin signaling may be the key pathway to the development of OA. However, direct genetic evidence for β-catenin in this disease has not been reported. Because tissue-specific activation of the β-catenin gene (targeted by Col2a1-Cre) is embryonic lethal, we specifically activated the β-catenin gene in articular chondrocytes in adult mice by generating β-catenin conditional activation (cAct) mice through breeding of β-cateninfx(Ex3)/fx(Ex3) mice with Col2a1-CreERT2 transgenic mice. Deletion of exon 3 of the β-catenin gene results in the production of a stabilized fusion β-catenin protein that is resistant to phosphorylation by GSK-3β. In this study, tamoxifen was administered to the 3- and 6-mo-old Col2a1-CreERT2;β-cateninfx(Ex3)/wt mice, and tissues were harvested for histologic analysis 2 mo after tamoxifen induction. Overexpression of β-catenin protein was detected by immunostaining in articular cartilage tissues of β-catenin cAct mice. In 5-mo-old β-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 β-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 β-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 β-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 β-catenin protein in the knee joint samples from patients with OA. These findings indicate that activation of β-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 β-catenin in the development of OA.

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