Regulating Fibrocartilage Stem Cells via TNF-α/Nf-κB in TMJ Osteoarthritis

Abstract

In this study, we investigate harnessing fibrocartilage stem cell (FCSC) capacities by regulating tumor necrosis factor α (TNF-α) signaling for cartilage repair in temporomandibular joint osteoarthritis (TMJOA). Stem cell specifics for FCSCs were characterized in the presence of TNF-α. Etanercept as a TNF-α inhibitor and BAY 11-7082 as an Nf-κB inhibitor were used to study TNF-α regulation of FCSCs. Lineage tracing was performed in Gli1-CreERT+;Tmfl/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-α/Nf-κB 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 μL, every 2 wk) or isometric vehicle. In vitro, TNF-α inhibited proliferation of FCSCs and increased FCSC apoptosis. TNF-α activation interfered with osteogenic and chondrogenic differentiation of FCSCs, while etanercept could partially recover FCSC specificity from TNF-α. FCSC lineage tracing in Gli1-CreERT+;Tmfl/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-κB pathway could significantly weaken the regulatory effect of TNF-α 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-α signaling reduced Nf-κB 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-α/Nf-κB inhibition promotes FCSC chondrogenic capacity for cartilage transformation in TMJOA.

Bioinspired Nanospheres as Anti-inflammation and Antisenescence Interfacial Biolubricant for Treating Temporomandibular Joint Osteoarthritis

“…TNF-α is a key factor in the pathogenesis and progression of osteoarthritis, and its level is increased in chronic inflammatory environment . This proinflammatory factor can regulate nuclear factor-κB pathway, enhance the releasing of matrix metalloproteinases such as MMP3 and MMP13, and impair chondrogenesis, therefore resulting in articular cartilage degradation in the development of TMJ osteoarthritis . Meanwhile, TNF-α is reported to contribute to cell aging, partially via the formation of oxidative stress .…”

“…42 This proinflammatory factor can regulate nuclear factor-κB pathway, enhance the releasing of matrix metalloproteinases such as MMP3 and MMP13, and impair chondrogenesis, therefore resulting in articular cartilage degradation in the development of TMJ osteoarthritis. 43 Meanwhile, TNF-α is reported to contribute to cell aging, partially via the formation of oxidative stress. 44 Intriguingly, MMP3, MMP13, and TNF-α are typical members of SASP, thus linking the proinflammatory and senescence-inducing effects of TNF-α.…”

Advances in Tissue Engineering of the Temporomandibular Joint Disc: An Overview of Current Status and Future Directions

“…Apart from this, other factors such as platelet derived growth factor, epidermal growth factor, interleukin-1, and tumor necrosis factor alpha also have role in proliferation, production of collagen, and glycosaminoglycans (GAG) [61]. In a recent study, Chen et al reported inhibition of TNF-α/Nf-κB promoted fibrocartilage stem cell's chondrogenic potential [62]. Kang et al in their study reported that TGF-β1 and IGF-1 induced increase in type 1 collagen and GAG synthesis and cells proliferation [63].…”

Drug delivery systems for treatment of temporomandibular joint osteoarthritis

“…Some studies develop PLGA-based microparticle formulations to carry anti-inflammatory RNAs to extend their residence time in the TMJ cavity ( Mountziaris et al, 2011 ). Tumor necrosis factor-α (TNF-α) is a kind of pro-inflammatory cytokines, which is expressed highly in the arthritic TMJs ( Bi et al, 2022 ). Mountziaris et al (2011) developed a TNF-α siRNA-PEI-PLGA microparticles and investigated their release kinetics.…”