Ectodysplasin-A deficiency exacerbates TMJOA by upregulating ATF4/Ihh signaling in mice

Ectodysplasin-A (EDA) has been reported to be involved in mouse condylar development, but the specific functions of EDA in maintaining homeostasis of the temporomandibular joint (TMJ) remain unclear. This study aimed to explore the underlying roles and related mechanisms of EDA in temporomandibular joint osteoarthritis (TMJOA).

The TMJOA mouse model was established by unilateral discectomy and the alteration of EDA expression was detected. EDA knockout male mice and their wild-type male littermates were used to clarify the effect of EDA on TMJOA. Mouse condylar chondrocytes were extracted to explore the potential mechanisms. The effects of local injection of supplementary EDA on condyles were also evaluated morphologically and histologically.

The expression of EDA was downregulated in condylar cartilage after TMJOA modeling. EDA deficiency aggravated degeneration and inflammation of condylar cartilage in TMJOA mice. In vitro studies demonstrated that EDA deficiency upregulated the expression of inflammatory cytokines, while supplementary EDA exhibited anticatabolic and anti-inflammatory effects on tumor necrosis factor-α (TNFα)-treated mouse condylar chondrocytes. Mechanistically, EDA deficiency effectively activated activating transcription factor 4 (ATF4) to upregulate Indian hedgehog (Ihh) signaling pathway and thereby aggravated the inflammation. Inhibition of ATF4 resulted in blocking of Ihh signaling. The selective pharmacological inhibition of Ihh signaling attenuated TNF-α-induced chondrocyte destruction and the release of inflammatory cytokines. Furthermore, intra-articular application of EDA significantly alleviated the osteoarthritic cartilage destruction after discectomy.

EDA deficiency aggravated TMJOA by modulating ATF4/Ihh pathway, which confirmed the essential role of EDA in maintaining TMJ cartilage homeostasis and its potential application in TMJOA treatment.