期刊
JOURNAL OF DENTAL RESEARCH
卷 101, 期 3, 页码 312-322出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/00220345211037248
关键词
cartilage; cell signaling; cytokine; joint disease; regenerative medicine; cell differentiation
资金
- National Natural Science Foundation of China [81771097, 82071139, 81801003, 81800928]
- Science and Technology Department of Sichuan Province in China [2020YJ0045]
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.
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.
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