Activation of \u03b2-catenin signaling in aggrecan-expressing cells in temporomandibular joint causes osteoarthritis-like defects

Tianqian Hui,Lan Zhao,Shanxing Zhang,Tingyu Wang,Ling Ye,Yachuan Zhou,Jun Li,Jianhong Gu,Di Chen,Lifan Liao

doi:10.1038/s41368-018-0016-z

Abstract

β-Catenin plays a critical role in cartilage formation and development. To further understand the role of β-catenin in osteoarthritis (OA) development in temporomandibular joint (TMJ), we have generated β-catenin conditional activation mice (β-cat(ex3)Agc1CreER) by breeding Agc1-CreER mice with β-cateninflox(ex3)/+ mice. Results of histologic analysis showed the progressive TMJ defects in 3- and 6-month-old β-cat(ex3)Agc1CreER mice (tamoxifen induction was performed at 2 weeks of age), including decreased chondrocyte numbers in the superficial layer associated with less Alcian blue staining, increased numbers of hypertrophic chondrocytes in deep layers, and rough articular surface. Compared to the TMJ phenotype of β-cat(ex3)Col2CreER mice, β-cat(ex3)Agc1CreER mice showed much severe morphological defects in the superficial layer of TMJ. This may reflect that Agc1-CreER mice could efficiently target cells in the superficial layer of TMJ. Results of immunostaining showed significantly increased expression of MMP13, Col-X, Adamts4, and Adamts5 in TMJ of β-cat(ex3)Agc1CreER mice. Results of proliferating cell nuclear antigen (PCNA), Ki67, and terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) staining further demonstrated that cell proliferation was decreased and cell apoptosis was increased in condylar cartilage of β-cat(ex3)Agc1CreER mice. Our findings indicate that abnormal upregulation of β-catenin in TMJ leads to defects assembling to OA-like phenotype, further demonstrating that β-catenin plays a critical role in TMJ pathogenesis.

Highlights

The temporomandibular joint (TMJ) is one of the most common sites affected by osteoarthritis (OA)
The Agc1-CreERT2 transgenic mouse model is a valuable tool to investigate the postnatal OA development, allowing chondrocyte-specific gene targeting in an inducible manner.[24]
To determine the role of β-catenin in TMJ OA development in postnatal mice, we decided to induce β-catenin expression in 2-week-old mice. β-Catenin was activated in mature chondrocytes. β-cat(ex3)Agc1CreER mice exhibited TMJ phenotype similar to that of human TMJ OA, including increased chondrocyte hypertrophy observed in the superficial zone of the condylar cartilage, severe loss of articular cartilage at the margins of cartilage tissue, and subchondral sclerosis

Summary

Introduction

The temporomandibular joint (TMJ) is one of the most common sites affected by osteoarthritis (OA). Canonical Wnt/β-catenin signaling plays an important role in the development and progression in multiple forms of arthritis, such as OA,[7] spondyloarthritis,[8,9,10] and diffuse idiopathic skeletal hyperostosis.[11,12,13] It has been shown that conditional activation of β-catenin in knee joint cartilage and intervertebral disc cartilage leads to knee OA and disc tissue degeneration.[7,14] In most recent studies, we found that activation of β-catenin signaling in facet joint causes severe OA-like phenotype (unpublished data). Our goal is to have comprehensive understanding of the role of Wnt/β-catenin signaling in the pathogenesis of arthritis

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