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. 2025 Feb;44(2):811-822.
doi: 10.1007/s10067-024-07281-z. Epub 2025 Jan 7.

1,25(OH)2D3 induces chondrocyte autophagy and reduces the loss of proteoglycans in osteoarthritis through inhibiting the NF-κB pathway

Pingping Liu  1   2 , Junxian Zhou  1 , Haigang Cui  3 , Jianhua Xu  1 , Guangfeng Ruan  4 , Changhai Ding  4 , Kang Wang  5
Affiliations

1,25(OH)2D3 induces chondrocyte autophagy and reduces the loss of proteoglycans in osteoarthritis through inhibiting the NF-κB pathway

Pingping Liu et al. Clin Rheumatol. 2025 Feb.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: NF-κB; Osteoarthritis; Signaling pathway; Vitamin D; Vitamin D receptor.

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Conflict of interest statement

Compliance with ethical standards. Disclosures: None. Statement of ethics and consent: All procedures were approved by the Experimental Animal Ethics Committee of Anhui Medical University (Approval No: LLSC20211506). Consent for sample procurement was obtained from the donors, adhering strictly to the ethical guidelines of China and the principle of the Helsinki Declaration.

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