Cldn11 deficiency aggravates osteoarthritis by inhibiting Notch signalling in a Tspan5-dependent manner.

Abstract

As a prevalent degenerative condition affecting joints, osteoarthritis (OA) involves the gradual deterioration of articular cartilage. Impaired chondrocyte function is a major driver of osteoarthritis pathogenesis. In this study, we focused on deciphering the mechanistic basis of Tspan5 activity in the absence of the tight junction component Claudin11(Cldn11), utilizing male SD rats as the experimental model, which regulates the process of OA through the Notch signalling pathway. An animal model of OA was successfully established by injecting monosodium iodoacetate (MIA) into the knee joint cavity. The rats in the experimental groups were injected with Cldn11-RNAi lentivirus into the knee joint cavity or orally gavaged with Notch signalling pathway-specific inhibitors. The mechanical pain threshold was monitored dynamically using the von Frey fiber filament method. The OA model group exhibited a significant decrease in Cldn11 levels, as confirmed by qRT-PCR, western blot, and immunohistochemical staining, alongside this, the levels of essential Notch signalling molecules declined. Gene downregulation of Cldn11 significantly inhibited the expression of Tspan5 and further downregulated Notch signalling pathway activity, accelerating the process of cartilage degeneration. The Notch inhibitor intervention group presented a significant reduction in the mechanical pain threshold. The present study demonstrated that Cldn11 knockdown transcriptionally suppresses Tspan5 expression, leading to a Tspan5-dependent attenuation of the Notch pathway, which ultimately exacerbates the pathogenesis of osteoarthritis.