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Background <p>Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling. Toll-like receptors (TLRs), particularly TLR4, are pivotal in driving the inflammatory responses central to OA pathogenesis. The RNA-binding protein MEX3B is implicated in post-transcriptional regulation, but its role in OA remains unexplored.</p> Methods <p>Bioinformatic analysis of the GSE114007 dataset identified differentially expressed RNA-binding proteins in OA cartilage. MEX3B expression was validated in human OA tissues. In vitro, an inflammatory model was established in primary murine chondrocytes using lipopolysaccharide (LPS). The functional role of MEX3B was assessed through knockdown experiments, evaluating its impact on TLR4 expression, NF-κB pathway activation (measured by p-p65 and p-IκBα levels), and the expression of inflammatory cytokines (IL-1α, TNF-α) and cartilage-degrading enzymes (ADAMTS5, MMP13). Mechanistically, RNA immunoprecipitation and domain-deletion assays were employed to confirm the direct binding of MEX3B to TLR4 mRNA via its KH domain. In vivo, the protective effect of MEX3B knockout was evaluated in a murine ACLT model, with or without intra-articular administration of the TLR4 agonist monophosphoryl lipid A (MPLA).</p> Results <p>MEX3B was significantly upregulated in OA cartilage. Its knockdown in chondrocytes suppressed TLR4 expression at both mRNA and protein levels, impaired TLR4 membrane localization, and inhibited the NF-κB pathway. This led to a marked reduction in inflammatory mediators and catabolic factors. Mechanistically, MEX3B directly binds to TLR4 mRNA through its KH domain, leading to increased TLR4 protein levels and pathway activation. In vivo, MEX3B deficiency mitigated OA progression, which was effectively reversed by the TLR4 agonist MPLA.</p> Conclusion <p>Our study unveils a novel mechanism whereby MEX3B, by post-transcriptionally regulating TLR4 expression, activates the NF-κB signaling cascade, thereby promoting inflammation and cartilage breakdown in OA. These findings position MEX3B as a promising therapeutic target for intervening in the inflammatory process of OA.</p> Graphical abstract

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MEX3B aggravates osteoarthritis progression by post-transcriptionally activating TLR4-NF-κB signaling axis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月4日

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  • Zeze Fu,
  • Yanfeng Huang,
  • Siqi Zhang,
  • Jian Chen

摘要

Background

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling. Toll-like receptors (TLRs), particularly TLR4, are pivotal in driving the inflammatory responses central to OA pathogenesis. The RNA-binding protein MEX3B is implicated in post-transcriptional regulation, but its role in OA remains unexplored.

Methods

Bioinformatic analysis of the GSE114007 dataset identified differentially expressed RNA-binding proteins in OA cartilage. MEX3B expression was validated in human OA tissues. In vitro, an inflammatory model was established in primary murine chondrocytes using lipopolysaccharide (LPS). The functional role of MEX3B was assessed through knockdown experiments, evaluating its impact on TLR4 expression, NF-κB pathway activation (measured by p-p65 and p-IκBα levels), and the expression of inflammatory cytokines (IL-1α, TNF-α) and cartilage-degrading enzymes (ADAMTS5, MMP13). Mechanistically, RNA immunoprecipitation and domain-deletion assays were employed to confirm the direct binding of MEX3B to TLR4 mRNA via its KH domain. In vivo, the protective effect of MEX3B knockout was evaluated in a murine ACLT model, with or without intra-articular administration of the TLR4 agonist monophosphoryl lipid A (MPLA).

Results

MEX3B was significantly upregulated in OA cartilage. Its knockdown in chondrocytes suppressed TLR4 expression at both mRNA and protein levels, impaired TLR4 membrane localization, and inhibited the NF-κB pathway. This led to a marked reduction in inflammatory mediators and catabolic factors. Mechanistically, MEX3B directly binds to TLR4 mRNA through its KH domain, leading to increased TLR4 protein levels and pathway activation. In vivo, MEX3B deficiency mitigated OA progression, which was effectively reversed by the TLR4 agonist MPLA.

Conclusion

Our study unveils a novel mechanism whereby MEX3B, by post-transcriptionally regulating TLR4 expression, activates the NF-κB signaling cascade, thereby promoting inflammation and cartilage breakdown in OA. These findings position MEX3B as a promising therapeutic target for intervening in the inflammatory process of OA.

Graphical abstract