Activation of β-catenin in Temporomandibular Joint Causes Osteoarthritis-like Defects

Objectives: β-catenin plays a critical role in cartilage formation and development. Dysregulation of β-catenin (conditional activation, targeted by Col2-CreER transgenic mice) causes cartilage degeneration and osteoarthritis (OA) development in knee, spine and temporomandibular joint (TMJ). To further understand the role of β-catenin signaling in OA development in TMJ we have generated and analyzed β-catenin(ex3)^Agc1ER transgenic mice and determined if activation of β-catenin in aggrecan-expressing articular cartilage cells could affect the homeostasis of TMJ tissue.
Methods: Agc1-CreER transgenic mice were bred with ROSA^mT/mG reporter mice to determine Cre recombination efficiency. Agc1-CreER mice were then crossed with β-catenin^{flox (ex3)/+} mice to generate β-catenin conditional activation mice. TMJ samples were harvested when the mice were at 3- and 6-month-old. The sections were evaluated by histology with Alcian blue/H&E (AB/ H&E) staining. Expression of MMP13, the primary enzyme responsible for cartilage degeneration, was detected by immunohistochemistry. Expression of ADAMTS 4, ADAMTS 5 and the marker gene of chondrocyte hypertrophy, COLX was examined by immunofluorescence. PCNA and tunel staining was performed to evaluate cell proliferation and apoptosis.
Results: High levels of Cre-recombination were seen in Agc1-CreER;ROSA^mT/mG mice. Progressive TMJ defects developed in 3- and 6-month-old β-catenin(ex3)^AggrecanER mice, as revealed by histology, including decreased chondrocyte numbers in the superficial layer associated with less Alcian blue staining, increased hypertrophic chondrocytes in the deep layers, rough articular surface and osteophyte formation. Results of IHC and IF showed significantly increased expression of MMP13, COLX, ADAMTS4 and ADAMTS5 in TMJ tissue of β-catenin(ex3)^Agc1ER mice. PCNA and tunel staining demonstrated that cell proliferation was decreased and cell apoptosis was increased in mutant mice.
Conclusions: Our findings indicate that abnormal up-regulation of β-catenin in TMJ cartilage leads to defects assembling to an OA-like phenotype, suggesting that β-catenin plays a critical role in TMJ pathogenesis.