Unraveling the crucial role of SDF-1 in osteoarthritis progression: IL6/HIF-1α positive feedback and chondrocyte ferroptosis

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-09 DOI:10.1016/j.intimp.2025.114400

Tengyun Yang, Xianguang Yang, Guoliang Wang, Di Jia, Yanlin Li

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引用次数: 0

Abstract

Background

Osteoarthritis (OA) is a common joint disease with an incompletely understood pathogenesis. SDF-1, a key factor in cartilage matrix degradation, is involved in OA cartilage degeneration, yet its mechanism, especially regarding ferroptosis, remains unclear. This study focuses on elucidating the role of SDF-1-induced chondrocyte ferroptosis and the IL6/HIF-1α signalling axis in OA.

Methods

A rabbit OA model was created via SDF-1 induction. Knee cartilage tissues were sequenced and analyzed bioinformatically to identify key genes, and explore critical pathways. Clinical tissue samples were utilized to validate their clinical relevance. Furthermore, cell and rabbit models were constructed through gene interference and pathway blocking. The expression of related genes and proteins was detected by QPCR, ELISA, Western blot, and immunofluorescence. Additionally, OA and ferroptosis indicators such as cell viability, immunohistochemistry, ROS, lipid ROS, Fe²⁺, MDA, and mitochondrial morphology were evaluated to uncover the molecular mechanism by which SDF-1 regulates the IL6/HIF-1α signalling axis to mediate chondrocyte ferroptosis.

Results

Bioinformatics revealed that ferroptosis was significantly activated in SDF-1-induced OA, with IL6 and HIF-1 pathways implicated. In vitro and in vivo, SDF-1 increased the expression and secretion of MMP13 but decreased COL2A1 and ACAN in chondrocytes, leading to OA-like changes. It also suppressed the expression levels of SLC7A11 and GPX4, upregulated the gene and protein levels of ACSL4, promoted the accumulation of MDA, Fe²⁺, and ROS, and caused mitochondrial morphological changes. These ferroptosis manifestations could be alleviated by the ferroptosis inhibitor Fer-1. IL6 was an important mediator of SDF-1-induced ferroptosis, and knocking down IL6 also inhibited chondrocyte ferroptosis changes. Overexpressing IL6 (oeIL6) and using PX478 to inhibit the HIF-1 signalling pathway showed that PX478 could significantly relieve the cytotoxicity produced by the culture of oeIL6 and SDF-1, enhance chondrocyte viability, reverse the decreased expression of SLC7A11 and GPX4 caused by oeIL6, increase the expression of ACSL4, reverse the accumulation of MDA, Fe²⁺, and ROS. Moreover, PX478 could also significantly reduce the expression and secretion of IL6.

Conclusion

SDF-1 mediates chondrocyte ferroptosis via the IL6/HIF-1α positive feedback, promoting OA.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.