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Background <p>Mechanical overload‑related cytokines contribute to temporomandibular joint osteoarthritis (TMJOA) pathogenesis. This study investigated the role of overload‑associated platelet factor 4 (PF4).</p> Methods <p>Combined proteomic screening of human TMJOA synovial fluid (SF) and finite element simulation identified mechanically linked cytokines. A rat unilateral anterior crossbite (UAC) model was used to induce TMJ cartilage degeneration. To dissect the mechanism, primary rat TMJ chondrocytes were treated with PF4 and analyzed by transcriptomics and functional assays. Further, specific inhibitors targeting the canonical nuclear factor‑κB (NF-κB) pathway (TPCA-1) or TLR2 (C29) were applied in vitro to pinpoint the signaling cascade. Their potential therapeutic effects were further assessed by administration in the UAC model.</p> Results <p>Clinical samples revealed elevated PF4 levels in the SF of TMJOA patients, correlating with simulated mechanical stress at the condyle. In a rat UAC model, mechanical overload similarly upregulated PF4 in TMJ, concomitant with cartilage degeneration, anabolic-catabolic imbalance, and cellular senescence. In vitro, PF4 stimulation of primary chondrocytes suppressed anabolic markers while upregulating catabolic factors and senescence markers. Mechanistically, PF4 uniquely activated the canonical NF-κB pathway by directly engaging surface TLR2, bypassing its classical chemokine receptor C-X-C motif chemokine receptor 3 (CXCR3). This PF4-TLR2 interaction was both necessary and sufficient for downstream NF-κB-driven gene dysregulation. Notably, this PF4-TLR2 axis upregulates B-cell CLL/lymphoma 3 (BCL3), which in turn promotes pathway activation by accelerating early phosphorylation of p65, revealing an intrinsic feedback loop that fine-tunes the inflammatory response. In vivo, inhibition of TLR2 or canonical NF-κB signaling in the UAC model significantly mitigated overload-induced cartilage dysregulation and subchondral bone damage.</p> Conclusion <p>We delineate a novel mechanotransduction pathway in TMJOA, where overload-induced PF4 acts as an alarmin that signals through TLR2 to activate the canonical NF-κB cascade, a process further amplified by the downstream regulator BCL3, ultimately disrupting cartilage homeostasis. This work establishes the PF4-TLR2-NF-κB axis as a crucial pathogenic driver and a promising therapeutic target for load-related TMJ degeneration.</p> Graphical Abstract <p></p>

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PF4 drives mechanical overload-induced temporomandibular joint osteoarthritis through TLR2-dependent activation of NF-κB

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月22日

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  • Wei Sun,
  • Jiashun Wu,
  • Yu Liu,
  • Xiang Li,
  • Guozhong Zeng,
  • Kan Li,
  • Kai Su,
  • Juan Xia,
  • Guangsen Zheng

摘要

Background

Mechanical overload‑related cytokines contribute to temporomandibular joint osteoarthritis (TMJOA) pathogenesis. This study investigated the role of overload‑associated platelet factor 4 (PF4).

Methods

Combined proteomic screening of human TMJOA synovial fluid (SF) and finite element simulation identified mechanically linked cytokines. A rat unilateral anterior crossbite (UAC) model was used to induce TMJ cartilage degeneration. To dissect the mechanism, primary rat TMJ chondrocytes were treated with PF4 and analyzed by transcriptomics and functional assays. Further, specific inhibitors targeting the canonical nuclear factor‑κB (NF-κB) pathway (TPCA-1) or TLR2 (C29) were applied in vitro to pinpoint the signaling cascade. Their potential therapeutic effects were further assessed by administration in the UAC model.

Results

Clinical samples revealed elevated PF4 levels in the SF of TMJOA patients, correlating with simulated mechanical stress at the condyle. In a rat UAC model, mechanical overload similarly upregulated PF4 in TMJ, concomitant with cartilage degeneration, anabolic-catabolic imbalance, and cellular senescence. In vitro, PF4 stimulation of primary chondrocytes suppressed anabolic markers while upregulating catabolic factors and senescence markers. Mechanistically, PF4 uniquely activated the canonical NF-κB pathway by directly engaging surface TLR2, bypassing its classical chemokine receptor C-X-C motif chemokine receptor 3 (CXCR3). This PF4-TLR2 interaction was both necessary and sufficient for downstream NF-κB-driven gene dysregulation. Notably, this PF4-TLR2 axis upregulates B-cell CLL/lymphoma 3 (BCL3), which in turn promotes pathway activation by accelerating early phosphorylation of p65, revealing an intrinsic feedback loop that fine-tunes the inflammatory response. In vivo, inhibition of TLR2 or canonical NF-κB signaling in the UAC model significantly mitigated overload-induced cartilage dysregulation and subchondral bone damage.

Conclusion

We delineate a novel mechanotransduction pathway in TMJOA, where overload-induced PF4 acts as an alarmin that signals through TLR2 to activate the canonical NF-κB cascade, a process further amplified by the downstream regulator BCL3, ultimately disrupting cartilage homeostasis. This work establishes the PF4-TLR2-NF-κB axis as a crucial pathogenic driver and a promising therapeutic target for load-related TMJ degeneration.

Graphical Abstract