OSBPL2 deficiency impaired cochlear blood-labyrinth barrier via activation of NF-κB signaling pathway.

Abstract

OSBPL2 was one of the causal genes responsible for autosomal dominant non-syndromic hearing loss (DFNA) and the pathogenic mechanism of OSBPL2 mutations remain elusive. OSBPL2 was detected to be highly expressed in stria vascularis (SV) of mouse cochleae, in which the blood-labyrinth barrier (BLB) was located as an essential component of cochlear spiral duct. The present study explored a potential pathologic mechanism of OSBPL2 deficiency underlying the structural and functional impact on BLB. Osbpl2-knockout (KO) mice were used to characterize SV permeability, which was measured using FITC-dextran injection. OSBPL2-deficient human umbilical vein endothelial cells (HUVECs) were used to evaluate the endothelial permeability in vitro. Tight junctions (TJs) in SV and HUVECs were characterized using immunofluorescent staining. The results showed that significant SV leakage was detected in cochleae of 10-month-old Osbpl2-KO mice, which was consistent with the increased endothelial permeability in OSBPL2-deficient HUVECs. It was also noted that OSBPL2 deficiency led to TJs disruption and induced inflammation-mediated apoptosis via the activation of NF-κB signaling. This study revealed the potential pathogenic mechanism of OSBPL2 deficiency in SV lesion, which helped to elucidate the underlying pathogenesis of OSBPL2 mutations in DFNA.