Autophagy was involved in tumor necrosis factor-α-inhibited osteogenic differentiation of murine calvarial osteoblasts through Wnt/β-catenin pathway

Abstract

Periodontitis is an inflammatory disease with a high incidence characterized by irreversible destruction of alveolar bone. This study aimed to investigate the effect of tumor necrosis factor-α (TNF-α) on osteogenic differentiation and its molecular mechanism. TNF-α inhibited osteogenic differentiation as revealed by the lower accumulation of osteoblastic genes like runt-related transcription factor (Runx2), alkaline phosphatase (ALP), osteoprotegerin (OPG), and osteocalcin (OCN). Moreover, TNF-α down-regulated the expressions of LC3II, ATG7, and beclin 1 (BECN1); suggesting that autophagy was inhibited during the process of osteogenic differentiation. Consistently, Wnt/β-catenin signaling pathway members such as low-density lipoprotein receptor-related protein 5 (LRP5), β-catenin, and phosphorylated-β-catenin (p-β-catenin) were reduced by TNF-α. Furthermore, the inhibitory effect of TNF-α on osteogenic differentiation and the Wnt/β-catenin signaling pathway could be abated by autophagy inducers but exacerbated by autophagy inhibitors. The most intriguing finding of all was that TNF-α inhibited osteoblastic differentiation and the Wnt/β-catenin signaling pathway by down-regulating autophagy, and autophagy positively regulated the Wnt/β-catenin pathway and thus influenced osteoblastic differentiation. Our study provides a theoretical basis for autophagy-inducer therapy for the alveolar bone loss caused by periodontitis.