Regulating Fibrocartilage Stem Cells via TNF-alpha/Nf-kappa B in TMJ Osteoarthritis

In this study, we investigate harnessing fibrocartilage stem cell (FCSC) capacities by regulating tumor necrosis factor alpha (TNF-alpha) signaling for cartilage repair in temporomandibular joint osteoarthritis (TMJOA). Stem cell specifics for FCSCs were characterized in the presence of TNF-alpha. Etanercept as a TNF-alpha inhibitor and BAY 11-7082 as an Nf-kappa B inhibitor were used to study TNF-alpha regulation of FCSCs. Lineage tracing was performed in Gli1-CreERT(+);Tm-fl/fl mice when etanercept (1 mg/kg, every 3 d) or isometric vehicle was subcutaneously injected to trace specific changes in FCSCs. Surgically induced TMJOA Sprague-Dawley rats were generated with BAY 11-7082 (5 mg/kg, every 3 d) or vehicle subcutaneous injection to investigate the functional role of TNF-alpha/Nf-kappa B in TMJOA. Anterior disc displacement (ADD) rabbits were used to analyze the therapeutic effect of etanercept as a TMJOA intra-articular treatment with etanercept (0.02 mg in 100 mu L, every 2 wk) or isometric vehicle. In vitro, TNF-alpha inhibited proliferation of FCSCs and increased FCSC apoptosis. TNF-alpha activation interfered with osteogenic and chondrogenic differentiation of FCSCs, while etanercept could partially recover FCSC specificity from TNF-alpha. FCSC lineage tracing in Gli1-CreERT(+);Tm-fl/fl mice showed that the chondrogenic capacity of Gli1(+) cell lineage was markedly suppressed in osteoarthritis cartilage, the phenotype of which could be significantly rescued by etanercept. Specifically blocking the Nf-kappa B pathway could significantly weaken the regulatory effect of TNF-alpha on FCSC specificity in vitro and in TMJOA rats in vivo. Finally, intra-articular etanercept treatment efficiently rescued TMJ cartilage degeneration and growth retardation in ADD rabbits. Inhibition of TNF-alpha signaling reduced Nf-kappa B transcripts and recovered FCSC specificities. In vivo, etanercept treatment effectively rescued the osteoarthritis phenotype in TMJOA mice and ADD rabbits. These data suggest a novel therapeutic mechanism whereby TNF-alpha/Nf-kappa B inhibition promotes FCSC chondrogenic capacity for cartilage transformation in TMJOA.

Automated summary

This study found that regulating TNF-α signaling can enhance the chondrogenic capacity of FCSCs for cartilage repair in TMJOA. Etanercept and BAY 11-7082 were effective in restoring FCSC specificity, showing potential as therapeutic strategies for TMJOA.