Activation of β-catenin signalling leads to temporomandibular joint defects
1 Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY 14642, USA
2 Department of Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA
3 Liaoning University of Traditional Chinese Medicine, Liaoning 110847, China
4 Department of Oral Anatomy and Physiology and TMD, College of Stomatology, Fourth Military Medical University, Xi’an 710032, China
5 Department of Oral Biology, University of Illinois at Chicago College of Dentistry, Chicago, IL 60612, USA
*、Current address: Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT 06520, USA
§ These authors equally contributed to this paper
Abstract
Despite extensive research in knee and hip osteoarthritis (OA), the underlying mechanism of temporomandibular joint (TMJ) disorder remains largely unknown. The purpose of this study was to determine whether the constitutive activation of β-catenin in the middle and deep layers of the articular cartilage can compromise the homeostasis of this tissue in the TMJ.Col2CreERT2transgenic mice were bred withRosamT/mGreporter mice to determine Cre recombination efficiency.Col2CreERT2mice were then crossed withβ-cateninflox(ex3)+mice to generateβ-cateninconditional activation mice,β-catenin(ex3)Col2ER. TMJ samples were harvested when the mice were 1-, 3- or 6-month-old and evaluated using histology, histomorphometry and immunohistochemistry.β-catenin(ex3)Col2ERmice were further crossed withMmp13flox/floxandAdamts5-/-mice to generate (β-catenin(ex3)/Mmp13)Col2ERandβ-catenin(ex3)Col2ER)/Adamts5-/-double mutant mice to investigate the role ofMmp13andAdamts5in the development of TMJ disorder. High levels of Cre-recombination were seen inCol2CreERT2;RosamT/mGmice. Progressive TMJ defects developed in 1-, 3- and 6-month-oldβ-catenin(ex3)Col2ERmice, as revealed by histology and histomorphometry. Results further demonstrated that the defects observed inβ-catenin(ex3)Col2ERmice were significantly decelerated after deletion of theMmp13orAdamts5gene in (β-catenin(ex3)/Mmp13)Col2ERorβ-catenin(ex3)Col2ER/Adamts5-/-double mutant mice. In summary, we found that β-catenin is a critical gene in the induction of TMJ cartilage degeneration, and over-expressingβ-cateninin TMJ cartilage leads to defects assembling an OA-like phenotype. Deletion ofMmp13andAdamts5inβ-catenin(ex3)Col2ERmice ameliorates the development of TMJ defects. This study suggests thatMmp13andAdamts5could be potential therapeutic targets for the treatment of TMJ disorders.
Keywords
- Temporomandibular joint
- osteoarthritis
- β-catenin
- MMP13
- Adamts5
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