Liu Pingping, Zhou Junxian, Cui Haigang, Xu Jianhua, Ruan Guangfeng, Ding Changhai, Wang Kang
Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, China.
Department of Rheumatology and Immunology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, 362000, China.
Clin Rheumatol. 2025 Feb;44(2):811-822. doi: 10.1007/s10067-024-07281-z. Epub 2025 Jan 7.
Nuclear transcription factor-κB (NF-κB) activation is a pivotal event in the pathogenesis of osteoarthritis (OA). OA patients frequently exhibit vitamin D (VD) deficiency, which is commonly associated with NF-κB activation. Our study aimed to investigate whether VD could protect against OA by modulating NF-κB pathway and to explore the underlying mechanisms.
Proteins levels were assessed by western blot analysis, gene expression was quantified by quantitative real-time polymerase chain reaction (qRT‒PCR) in vivo and in vitro. The expression of phosphorylated-p65 (p-p65) in knee OA rats was detected by immunohistochemistry, and an NF-κB nuclear translocation assay was validated in chondrocytes. Immunoprecipitation was employed to detect the interaction between NF-κB and vitamin D receptor (VDR) in vivo and in vitro. Small interfering RNA (Si-NF-κB and Si-VDR) transfection was used to investigate the role of NF-κB and VDR signaling pathway in knee OA rats under VD influence. Cartilage changes were visualized of knee OA rats using hematoxylin and eosin as well as safranin-O/fast green of staining.
Our findings indicated that VD alleviates OA by inhibiting NF-κB pathway, which in turn reduces chondrocyte apoptosis and extracellular matrix (ECM) degradation. Further analysis revealed that VD primarily stabilizes NF-κB through the interaction of VDR and NF-κB, modulating the AMPK/mTOR signaling pathway to enhance autophagy and delay the progression of OA.
This study highlights the protective role of VD in OA by stabilization of NF-κB, mainly through the interaction between VDR and NF-κB. This interaction regulates the AMPK/mTOR signaling pathway, promoting autophagy and suggesting a potential therapeutic strategy for OA management. Key Points • VD confers a protective effect on OA by primarily stabilizing NF-κB through the interaction between VDR and NF-κB, which in turn inhibits NF-κB phosphorylation and nuclear translocation. • In chondrocytes, VD helps shield against OA by blocking NF-κB's entry into the nucleus, subsequently regulating autophagy via the AMPK/mTOR signaling pathway.
核转录因子-κB（NF-κB）激活是骨关节炎（OA）发病机制中的关键事件。OA患者常表现出维生素D（VD）缺乏，这通常与NF-κB激活有关。本研究旨在探讨VD是否可通过调节NF-κB途径预防OA，并探索其潜在机制。
通过蛋白质印迹分析评估蛋白质水平，在体内和体外通过定量实时聚合酶链反应（qRT-PCR）对基因表达进行定量。通过免疫组织化学检测膝骨关节炎大鼠中磷酸化-p65（p-p65）的表达，并在软骨细胞中验证NF-κB核转位测定。采用免疫沉淀法检测体内和体外NF-κB与维生素D受体（VDR）之间的相互作用。使用小干扰RNA（Si-NF-κB和Si-VDR）转染来研究NF-κB和VDR信号通路在VD影响下对膝骨关节炎大鼠的作用。使用苏木精和伊红以及番红O/固绿染色观察膝骨关节炎大鼠的软骨变化。
我们的研究结果表明，VD通过抑制NF-κB途径减轻OA，进而减少软骨细胞凋亡和细胞外基质（ECM）降解。进一步分析表明，VD主要通过VDR与NF-κB的相互作用稳定NF-κB，调节AMPK/mTOR信号通路以增强自噬并延缓OA的进展。
本研究强调了VD通过稳定NF-κB对OA的保护作用，主要是通过VDR与NF-κB之间的相互作用。这种相互作用调节AMPK/mTOR信号通路，促进自噬，并为OA管理提出了一种潜在的治疗策略。要点：•VD主要通过VDR与NF-κB之间的相互作用稳定NF-κB，从而对OA产生保护作用，进而抑制NF-κB磷酸化和核转位。•在软骨细胞中，VD通过阻止NF-κB进入细胞核来帮助抵御OA，随后通过AMPK/mTOR信号通路调节自噬。
