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中华关节外科杂志(电子版)

中华关节外科杂志(电子版) ›› 2026, Vol. 20 ›› Issue (03) : 322 -333. doi: 10.3877/cma.j.issn.1674-134X.2026.03.009

基础论著

滑膜巨噬细胞铁调素诱发软骨细胞铁死亡的机制研究
吉宇通1,2,3, 周月惠1,3, 卫杨文祥4, 陈镇秋5,6,7,8, 王海彬5,6,7,8, 周驰2,5,6,7,8,9,†()   
  1. 1　510405　广州中医药大学第一临床医学院
    2　510095　广州，广东省中医药研究开发重点实验室
    3　510388　广州中医药大学岭南医学研究中心
    4　510095　广州中医药大学第五临床医学院
    5　510405　广州中医药大学第一附属医院人工关节与髋关节科
    6　510405　广州，广东省中医临床研究院
    7　510405　广州，医疗机构中药制剂与中药新药转化广东省工程研究中心
    8　510405　广州，广东省岭南特色医院制剂转化工程技术研究中心
    9　525022　广东茂名，广州中医药大学茂名医院（茂名市中医院）关节骨科
  • 收稿日期:2025-12-12 出版日期:2026-06-01
  • 通信作者: 周驰
  • 基金资助:
    广东省中医药研究开发重点实验室开放基金项目(KFKT01-004); 广东省中医药局科研项目(20233001); 广东省医学科学技术研究基金项目(A2024056)

Mechanistic study on synovial macrophage-derived hepcidin inducing ferroptosis in chondrocytes

Yutong Ji1,2,3, Yuehui Zhou1,3, Yangwenxiang Wei4, Zhenqiu Chen5,6,7,8, Haibin Wang5,6,7,8, Chi Zhou2,5,6,7,8,9,†()   

  1. 1 The First Clinical Medical College of Guangzhou University of Chinese Medicine, Guangzhou 510405, China
    2 Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou 510095, China
    3 Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou 510388, China
    4 The Fifth Clinical College of Guangzhou, University of Chinese Medicine, Guangzhou 510095, China
    5 The First Affiliated Hospital of Guangzhou University of Chinese Medicine Artificial Joint and Hip Surgery Department, Guangzhou 510405, China
    6 Guangdong Clinical Research Academy of Chinese Medicine, Guangzhou 510405, China
    7 Guangdong Engineering Research Center of Commercialization of Medical Institution Preparations and Traditional Chinese Medicines, Guangzhou 510405, China
    8 Guangdong Engineering Technology Research Center of Commercialization of Lingnan Special Medical Institution Preparations, Guangzhou 510405, China
    9 Maoming Hospital of Guangzhou University of Chinese Medicine/Maoming Hospital of Traditional Chinese Medicine Orthopedic Joint Surgery, Maoming 525022, China
  • Received:2025-12-12 Published:2026-06-01
  • Corresponding author: Chi Zhou
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引用本文：

吉宇通, 周月惠, 卫杨文祥, 陈镇秋, 王海彬, 周驰. 滑膜巨噬细胞铁调素诱发软骨细胞铁死亡的机制研究[J/OL]. 中华关节外科杂志(电子版), 2026, 20(03): 322-333.

Yutong Ji, Yuehui Zhou, Yangwenxiang Wei, Zhenqiu Chen, Haibin Wang, Chi Zhou. Mechanistic study on synovial macrophage-derived hepcidin inducing ferroptosis in chondrocytes[J/OL]. Chinese Journal of Joint Surgery(Electronic Edition), 2026, 20(03): 322-333.

目的

探究滑膜巨噬细胞铁调素（hepcidin）与铁输出蛋白（FPN1）在膝骨关节炎软骨细胞铁死亡中的作用机制。

方法

动物实验：选取24只6～8周龄SD大鼠，采用随机数字表法随机分为假手术组与手术（改良Hulth手术）组，每组12只。假手术组仅切开关节囊，手术组复制膝骨关节炎模型。模型成功后酶联免疫吸附测定（ELISA）法检测大鼠血清铁调素表达变化，采用micro-CT观察大鼠膝关节形态结构变化，采用苏木精-伊红染色、甲苯胺蓝染色和番红O-固绿染色观察膝关节软骨组织的形态学变化，免疫组化法检测大鼠膝关节滑膜铁调素与软骨基质金属蛋白酶（MMP）3、Ⅱ型胶原蛋白（Col2a1）表达情况，免疫荧光技术检测膝关节软骨谷胱甘肽过氧化物酶4（GPX4）、核因子E2相关因子2（NRF2）表达情况。细胞实验：以白细胞介素（IL）-6干预RAW264.7细胞，探究IL-6诱导巨噬细胞分泌铁调素的最适浓度；采用IL-6干预RAW264.7细胞后的上清液干预软骨细胞，观察软骨细胞FPN1的表达；同时将软骨细胞分为空白对照组、模型组（铁调素处理）、阳性对照组（erastin处理），直接观察软骨细胞变化，western blot法检测巨噬细胞铁调素对软骨细胞FPN1的影响，免疫荧光技术检测氧化还原相关因子活性氧（ROS）表达，还原型谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）、丙二醛（malondialdehyde，MDA）、超氧化物歧化酶（superoxide dismutase，SOD）试剂盒检测氧化还原指标。采用单因素方差分析和t检验进行统计学分析。

结果

与假手术组相比，手术组构建的膝骨关节炎模型大鼠膝关节出现明显病理改变：micro-CT显示模型组关节间隙变窄、骨赘形成，骨体积分数（t=5.069，P＜0.001）、骨小梁数目（t=4.225，P＜0.05）及厚度（t=5.879，P＜0.001）显著降低，骨小梁分离度升高（t=2.691，P＜0.01），骨微结构破坏严重；手术组较假手术组的骨关节炎评分显著增加（t=7.778，P＜0.001），软骨组织染色可见层次紊乱、细胞排布稀疏、基质裂隙形成，Col2a1表达减少（t=4.931，P＜0.001），MMP3表达上调（t=17.35，P＜0.001），蛋白聚糖大量丢失。模型组大鼠血清及滑膜组织中铁调素表达显著升高，软骨组织中铁输出蛋白FPN1表达则明显下调（t=10.67，P＜0.001）；软骨组织中铁死亡核心抑制因子GPX4（t=15.93，P＜0.001）及抗氧化转录因子NRF2（t=14.26，P＜0.001）的表达水平显著降低。细胞实验显示，10 μg/L的IL-6可高效诱导RAW264.7细胞高表达铁调素，其10%条件培养基可显著抑制软骨细胞FPN1表达；铁调素干预软骨细胞后ROS蓄积，GSH/GSSG比值降低（F=395.1，P＜0.001），MDA表达水平升高（F=181.7，P＜0.001）、SOD活性下降（F=1 160，P＜0.001）。

结论

滑膜巨噬细胞来源铁调素抑制软骨细胞FPN1功能，引发软骨细胞铁蓄积，进而激活氧化应激-脂质过氧化通路，最终诱发膝骨关节炎软骨细胞发生铁死亡。

关键词: 膝骨关节炎, 滑膜巨噬细胞, 软骨细胞, 铁死亡
Objective

To explore the mechanism of synovial macrophage-derived hepcidin and iron exporter protein (FPN1) in chondrocyte ferroptosis of knee osteoarthritis (KOA).

Methods

Animal experiment: 24 SD rats of six to eight weeks old were selected and randomly divided using a random number tableinto the sham operation group (the sham group) and the modified-Hult surgery (M-Hult) group (the surgical group), 12 rats in each group. The sham group only incised the joint capsule, while the M-Hult group established a model of KOA. After the model was successful, enzyme linked immunosorbent assay (ELISA) was used to detect the changes in hepcidin expression in rat serum. Micro-CT was employed to observe the morphological and structural changes of the rat knee joints. Hematoxylin-eosin (HE) staining, toluidine blue staining and safranin O/fast green violet staining were used to observe the morphological changes of the knee joint cartilage tissue. Immunohistochemistry was used to detect the expression of hepcidin, matrix metalloproteinase (MMP3) and type Ⅱ collagen (Col2a1) in the knee joint synovium of rats. Immunofluorescence technique was used to detect the expression of glutathione peroxidase 4 (GPX4) and nuclear factor erythroid 2-related factor 2 (NRF2) in the knee joint cartilage. Cell experiment: RAW264.7 cells were treated with interleukin ( IL)-6 to investigate the optimal time and concentration for IL-6 to induce the secretion of hepcidin by macrophages; the supernatant obtained after IL-6 intervention on RAW264.7 cells was used to intervene chondrocytes, and the expression of FPN1 in chondrocytes was observed; the chondrocytes were divided into blank control group, model group (hepcidin treated), and positive control group (erastin treated). The changes in chondrocytes were directly observed, the effect of hepcidin in macrophages on FPN1 in chondrocytes was detected by western blot, the expression of redox-related factor reactive oxygen species (ROS) was detected by immunofluorescence technology, and the oxidative-reductive indicators were detected using glutathione/glutathione disulfide (GSH/GSSG), MDA, and SOD kits. Single factor variance analysis and t test were performed for data analysis.

Results

Compared with the sham group, the knee osteoarthritis model rats in the surgical group showed significant pathological changes in their knees: micro-CT revealed that the joint space in the model group narrowed, bone spurs formed, and the bone volume fraction (t=5.069, P<0.001), trabecular number (t=4.225, P<0.05), and thickness (t=5.879, P<0.001) significantly decreased, while the trabecular separation (t=2.691, P<0.01) increased, and the bone microstructure was severely damaged. Compared with the sham group, the osteoarthritis score in the surgical group was significantly elevated (t=7.778, P<0.001). Cartilage tissue staining revealed disorganized layers, sparse cell arrangement, and matrix fissure formation. Meanwhile, the expression of Col2a1 decreased (t=4.931, P<0.001), the expression of MMP3 upregulated (t=17.35, P<0.001), and a substantial loss of proteoglycans was observed. In the serum and synovial tissue of the model group rats, the expression of hepcidin significantly increased, while the expression of the iron export protein FPN1 in the cartilage tissue significantly down regulated (t=10.67, P<0.001). The expression levels of the ferroptosis core inhibitor GPX4 (t=15.93, P<0.001) and the antioxidant transcription factor NRF2 (t=14.26, P<0.001) in cartilage tissue were significantly decreased. Cell experiments demonstrated that 10 μg/L IL-6 could efficiently induce high expression of hepcidin in RAW264.7 cells, and its 10% conditioned medium could significantly inhibit the expression of FPN1 in chondrocytes. After hepcidin intervenes with chondrocytes, ROS accumulation occurs, the GSH/GSSG ratio decreases (F=395.1, P<0.001), the expression level of MDA increases (F=181.7, P<0.001), and the activity of SOD decreases (F=1160, P<0.001).

Conclusion

Hepcidin derived from synovial macrophages inhibits the function of FPN1 in chondrocytes, which triggers iron accumulation in chondrocytes, thereby activating the oxidative stress-lipid peroxidation pathway, and ultimately inducing ferroptosis of chondrocytes in KOA.

Key words: Knee Osteoarthritis, Synovial macrophages, Chondrocytes, Ferroptosis
图1 M-Hulth（改良Hulth手术）诱导KOA（膝骨关节炎）模型的关节结构及组织病理改变。图A为假手术组与手术组膝关节的Micro-CT3D重建图像及横截面图像（比例尺=5 mm）；图B为两组软骨下骨BV/TV（%）（骨体积/组织体积）定量分析；图C为两组软骨下骨Tb.N（骨小梁数量）定量分析；图D为两组软骨下骨Tb.Sp（骨小梁分离度）定量分析；图E为两组软骨下骨Tb.Th（骨小梁厚度）定量分析；图F为两组膝关节软骨组织HE（苏木精-伊红）染色（比例尺=100 μm）；图G为两组膝关节软骨组织TB染色（比例尺=100 μm）；图H为两组膝关节软骨组织SO&FG（番红O-固绿）染色（比例尺=100 μm）；图I为两组膝关节软骨组织GAGs相对含量比较；图J为两组膝关节软骨组织的OARSI评分比较；图K～L为两组膝关节组织中Col2a1的免疫组化染色（比例尺=100 μm）及平均光密度定量分析结果；图M～N为两组膝关节组织中MMP3的免疫组化染色（比例尺=100 μm）及平均光密度定量分析结果 注：*-P＜0.05；**-P＜0.01；***-P＜0.001；Col2a1-Ⅱ型胶原α1链；MMP-基质金属蛋白酶；HE-苏木精-伊红染色；TB-甲苯胺蓝染色；SO&FG-番红O-固绿染色；BV/TV-骨体积/组织体积；Tb.N-骨小梁数量；Tb.Sp-骨小梁分离度；Tb.Th-骨小梁厚度；GAGs-糖胺聚糖；OARSI-国际骨关节炎研究学会评分
Figure 1 Joint structure and histopathological changes in the modified-Hult surgery-induced KOA (knee osteoarthritis) model. A shows the 3D reconstructed images and cross-sectional images of the knee joints in the sham group and the surgical group (scale=5 mm); B is quantitative analysis on BV/TV (%) (bone volume/tissue volume) of subchondral bone in the two groups; C is quantitative analysis on Tb.N (the number of trabeculae) of subchondral bone in the two groups; D is quantitative analysis on Tb.Sp (separation degree of trabeculae)of subchondral bone in the two groups; E is quantitative analysis on Tb.Th (the thickness of trabeculae) of subchondral bone in the two groups; F is HE staining of the knee joint cartilage tissue in the two groups (scale=100 μm); G is TB staining of the knee joint cartilage tissue in the two groups (scale=100 μm); H is SO&FG staining of the knee joint cartilage tissue in the two groups (scale=100 μm); I is the relative content of GAGs analysis in the two groups; J is the histological score of OARSI; K and L are the results of immunohistochemical staining (scale=100 μm) and quantitative analysis of Col2a1 in the knee joint tissues of the two groups; M and N are results of immunohistochemical staining (scale=100 μm) and quantitative analysis of MMP3 in the knee joint tissues of the two groups Note: *-P＜0.05; **-P＜0.01; ***-P＜0.001; Col2a1-type Ⅱcollagen alpha one chain; MMP-matrix metalloproteinase; HE-hematoxylin-eosin staining; TB-toluidine blue staining; SO&FG-safranin O-gentian violet staining; BV/TV-bone volume / tissue volume; Tb.N-trabecular bone number; Tb.Sp-trabecular separation degree; Tb.Th-trabecular thickness; GAGs-glycosaminoglycans; OARSI-Osteoarthritis Research Society International score
图2 假手术组与手术组膝关节组织中GPX4（谷胱甘肽过氧化物酶4）及NRF2（核因子E2相关因子2）的免疫荧光染色结果。图A为假手术组与手术组中谷胱甘肽过氧化物酶4（GPX4）的免疫荧光染色（绿色荧光代表GPX4，蓝色为DAPI细胞核染色，Merge为荧光叠加图）（比例尺=100 μm）；图B为两组中NRF2的免疫荧光染色（绿色荧光代表NRF2，蓝色为DAPI细胞核染色，Merge为荧光叠加图）（比例尺=100 μm）；图C为GPX4荧光染色相对强度定量分析；图D为NRF2荧光染色相对强度定量分析 注：***-P＜0.001；GPX4-谷胱甘肽过氧化物酶4；NRF2-核因子E2相关因子2；DAPI-4’, 6-二脒基-2-苯基吲哚（细胞核染料）
Figure 2 Immunofluorescence staining results of GPX4 and NRF2 in the knee joint tissues of the sham group and the surgical group. A shows the immunofluorescence staining of glutathione peroxidase 4 (GPX4) in the Sham group and the M-Hult group (green fluorescence represents GPX4, blue is DAPI nuclear staining, Merge is the fluorescence superimposition image) (scale=100 μm); B shows the immunofluorescence staining of NRF2 in the two groups (green fluorescence represents NRF2, blue is DAPI nuclear staining, Merge is the fluorescence superimposition image) (scale=100 μm); C is the quantitative analysis on the relative intensity of fluorescence staining for GPX4; D is the quantitative analysis on the relative intensity of fluorescence staining for NRF2 Note: ***-P＜0.001; GPX4-glutathione peroxidase 4; NRF2-nuclear factor E2-related factor 2; DAPI-4’, 6-diaminobiphenylindole (nuclear stain)
图3 铁代谢相关分子在膝骨关节炎模型及不同处理条件下的表达特征。图A为假手术组与手术组膝关节组织中铁调素、FPN1（膜铁输出蛋白）的免疫组化染色结果（箭头指示阳性表达区域，比例尺=100 μm）；图B为两组大鼠血清游离铁调素的相对表达水平定量分析；图C、D为两组免疫组化阳性表达定量分析结果，即单位面积内（每mm²）FPN1与铁调素阳性细胞的数量；图E为不同浓度IL-6（0～100 μg/L）处理下铁调素蛋白质印迹结果；图F为不同浓度条件培养基（0%～30%）处理后FPN1的蛋白质印迹结果；图G为不同浓度IL-6（0～100 μg/L）处理后铁调素的蛋白相对表达水平；图H为不同浓度条件培养基（0%～30%）处理后FPN1的蛋白相对表达水平 注：***-P＜0.001；hepcidin-铁调素；FPN1-膜铁输出蛋白；IL-6-白细胞介素6；CM-条件培养基（以10 μg/L IL-6干预的RAW264.7上清液，与DMEM/F12完全培养基按不同浓度混合）；β-Actin-β-肌动蛋白（内参蛋白）
Figure 3 Expression characteristics of iron metabolism-related molecules in the knee osteoarthritis model under different treatment conditions. A shows immunohistochemical staining of hepcidin and FPN1 (ferroportin 1) in the knee joint tissues of the sham group and the surgical group (arrows indicate positive expression areas, scale bar=100 μm); B shows the quantitative analysis of relative serum free hepcidin levels in the two groups of rats; Figures C and D show the quantitative analysis results of immunohistochemical positive expression in the two groups (the number of FPN1-and hepcidin-positive cells per unit area (mm2); E shows the western blot results of hepcidin under different concentrations of IL-6 (0 to 100 μg/L); F shows the western blot results of FPN1 under different concentrations of conditioned medium (0% to 30%); G shows the relative protein expression levels of hepcidin under different concentrations of IL-6 (0 to 100 μg/L); H shows the relative protein expression levels of FPN1 under different concentrations of conditioned medium (0% to 30%) Note: ***-P<0.001; hepcidin-iron regulatory protein; FPN1-membrane iron efflux protein; IL-6-interleukin 6; CM-conditioned medium (the supernatant of RAW264.7 cells treated with IL-6 of 10 μg/L, mixed with DMEM/F12 complete medium at different concentrations); β-actin-β-actin (reference protein)
图4 不同处理组细胞中ROS（活性氧）及氧化应激相关指标的检测结果。图A为对照组、铁调素组、erastin（铁死亡诱导剂）处理组的ROS免疫荧光染色结果，绿色荧光示ROS，蓝色荧光示细胞核，Merge为荧光叠加图（比例尺=200 μm）；图B为ROS荧光染色定量分析；图C为各组细胞中GSH/GSSG（还原型谷胱甘肽/氧化型谷胱甘肽）比值定量分析；图D为各组细胞中丙二醛水平（μmol/mg）的定量分析；图E为各组细胞中SOD（超氧化物歧化酶）催化活性的定量分析 注：*-P＜0.05，**-P＜0.01，***-P＜0.001，ns-差异无统计学意义；NC-空白对照组；铁调素组-铁调素处理细胞；Erastin-铁死亡诱导剂erastin处理细胞；ROS-活性氧；DAPI-4’，6-二脒基-2-苯基吲哚（细胞核染料）；GSH/GSSG-还原型谷胱甘肽/氧化型谷胱甘肽；MDA-丙二醛；SOD-超氧化物歧化酶
Figure 4 Detection results of ROS (reactive oxygen species) and oxidative stress-related indicators in cells of different treatment groups. A shows the results of ROS immunofluorescence staining for the control group, the ferrostatin treatment group (Hep), and the erastin (ferroptosis inducer) treatment group, green fluorescence presents ROS, blue fluorescence presents cell nucleus, Merge is the fluorescence superimposition image, scale=200 μm); B is the quantitative analysis of ROS fluorescence staining; C is the quantitative analysis of GSH/GSSG ratio in each groups; D is the quantitative analysis of the malondialdehyde level (μmol/mg) in each group; E is the quantitative analysis of the catalytic activity of superoxide dismutase in each group Note: *-P<0.05, **-P<0.01, ***-P<0.001, ns-no statistically significant difference; NC-control group without treatment; hepcidin group-model group; erastin-positive control group; ROS-reactive oxygen species; DAPI-4’, 6-diamidino-2-phenylindole (nucleus dye); GSH/GSSG-reduced glutathione/oxidized glutathione; MDA-malondialdehyde; SOD-superoxide dismutase
图5 本研究中体内动物实验、体外细胞实验的关键设计环节及分子调控路径。左侧为体内动物实验体系，中间为体外细胞实验体系，右侧为核心分子的机制转导过程 注：IL-6-白细胞介素6；hepcidin-铁调素；FPN1-膜铁输出蛋白；Fe2+-亚铁离子；HE-苏木精-伊红染色；TB-甲苯胺蓝染色；SO/FG-番红O-固绿染色；ROS-活性氧；MDA-丙二醛；SOD-超氧化物歧化酶；GSH/GSSG-还原型谷胱甘肽/氧化型谷胱甘肽
Figure 5 Key design elements and molecular regulatory pathways of in vivo animal experiments and in vitro cell experiments in this study. The left side shows the in vivo animal experiment system, the middle part presents the in vitro cell experiment system, and the right side illustrates the mechanism transduction process of core molecules Note: IL-6-interleukin-6; hepcidin-hepcidin; FPN1-ferroportin 1; Fe2+-ferrous ion; HE-hematoxylin-eosin staining; TB-toluidine blue staining; SO/FG-safranin O-fast green staining; ROS-reactive oxygen species; MDA-malondialdehyde; SOD-superoxide dismutase; GSH/GSSG-reduced glutathione/oxidized glutathione
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