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[1]方偉華,莊至坤,彭鵬,等.激素性股骨頭壞死滑膜病變分子機制的實驗研究[J].中醫(yī)正骨,2024,36(09):49-58,75.
　FANG Weihua,ZHUANG Zhikun,PENG Peng,et al.Molecular mechanisms of synovial lesions in steroid-induced osteonecrosis of the femoral head:an experimental study[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2024,36(09):49-58,75.
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激素性股骨頭壞死滑膜病變分子機制的實驗研究()
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《中醫(yī)正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第36卷
期數:
2024年09期
頁碼:
49-58,75
欄目:
技術研究
出版日期:
2024-09-20

文章信息/Info

Title:
Molecular mechanisms of synovial lesions in steroid-induced osteonecrosis of the femoral head:an experimental study
作者:
方偉華1; 莊至坤2; 彭鵬1; 肖方駿1; 楊曉強1; 林錕1; 何偉3; 魏秋實3; 何敏聰3
(1.廣州中醫(yī)藥大學第三臨床醫(yī)學院,廣東 廣州 510006; 2.泉州市正骨醫(yī)院,福建 泉州 362000; 3.廣州中醫(yī)藥大學第三附屬醫(yī)院,廣東 廣州 510378)
Author(s):
FANG Weihua1; ZHUANG Zhikun2; PENG Peng1; XIAO Fangjun1; YANG Xiaoqiang1; LIN Kun1; HE Wei3; WEI Qiu-shi3; HE Mincong3
1.The Third Clinical Medical College of Guangzhou University of Chinese Medicine,Guangzhou 510006,Guangdong,China 2.Quanzhou Orthopedic-Traumatological Hospital,Quanzhou 362000,Fujian,China 3.The Third Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou 510378,Guangdong,China
關鍵詞:
股骨頭壞死;  糖皮質激素;  滑膜炎;  RNA測序;  成纖維細胞;  干擾素Ⅰ型
Keywords:
femur head necrosis;  glucocorticoids;  synovitis;  RNA-seq;  fibroblasts;  interferon typeⅠ
摘要:
目的:探討激素性股骨頭壞死(steroid-induced osteonecrosis of the femoral head,SONFH)滑膜病變的分子機制。方法:①轉錄組測序及生物信息學分析。收集9例接受全髖關節(jié)置換術的患者(SONFH患者3例、髖骨關節(jié)炎患者3例和股骨頸骨折患者3例)術中切除的髖關節(jié)滑膜組織,進行轉錄組測序和生物信息學分析,篩選SONFH滑膜病變核心基因。②滑膜組織檢測。根據標本來源將髖關節(jié)滑膜組織分為SONFH組、髖骨關節(jié)炎組和股骨頸骨折組。觀察各組髖關節(jié)滑膜組織的組織形態(tài),采用實時定量PCR檢測3組髖關節(jié)滑膜組織中SONFH滑膜病變核心基因的mRNA相對表達量,采用蛋白質印跡法和免疫組織化學染色法檢測3組髖關節(jié)滑膜組織中SONFH滑膜病變核心基因的蛋白相對表達量。采用免疫熒光染色法檢測SONFH滑膜病變的靶細胞。③細胞驗證。培養(yǎng)大鼠滑膜成纖維細胞,構建滑膜炎細胞模型。采用實時定量PCR及蛋白質印跡法檢測空白細胞(空白細胞組)和滑膜炎模型細胞(模型細胞組)中SONFH滑膜病變核心基因的表達。結果:①轉錄組測序和生物信息學分析結果。經對不同患者來源的髖關節(jié)滑膜組織進行差異基因分析,共篩選出1001個與SONFH髖關節(jié)滑膜病變相關的基因,這些基因與免疫反應和外泌體有關,其中干擾素調節(jié)因子(interferon regulatory factor,IRF)4和IRF7是SONFH髖關節(jié)滑膜病變的核心基因,兩者均為參與Ⅰ型干擾素應答的關鍵轉錄因子。②滑膜組織形態(tài)觀察結果。蘇木素-伊紅染色顯示,股骨頸骨折組髖關節(jié)滑膜組織形態(tài)正常,無細胞增生、肥大或間質水腫; 髖骨關節(jié)炎組髖關節(jié)滑膜組織細胞增生,有少量新生血管和細胞聚集; SONFH組髖關節(jié)滑膜組織細胞大量增殖和聚集,有新生血管。③滑膜組織中SONFH滑膜病變核心基因表達檢測結果。SONFH組髖關節(jié)滑膜組織中IRF4、IRF7、干擾素-α(interferon-α,IFN-α)的mRNA相對表達量均高于股骨頸骨折組和髖骨關節(jié)炎組(P=0.000,P=0.000,P=0.000; P=0.001,P=0.000,P=0.036),髖骨關節(jié)炎組髖關節(jié)滑膜組織中IRF4、IRF7、IFN-α的mRNA相對表達量均高于股骨頸骨折組(P=0.000,P=0.000,P=0.000)。IRF4、IRF7、IFN-α蛋白在SONFH組髖關節(jié)滑膜組織中高表達,SONFH組髖關節(jié)滑膜組織中IRF4、IRF7、IFN-α的蛋白相對表達量均高于股骨頸骨折組和髖骨關節(jié)炎組(P=0.001,P=0.000,P=0.000; P=0.000,P=0.014,P=0.000),髖骨關節(jié)炎組髖關節(jié)滑膜組織中IRF4、IRF7、IFN-α的蛋白相對表達量均高于股骨頸骨折組(P=0.002,P=0.005,P=0.000)。④SONFH滑膜病變靶細胞檢測結果。SONFH組髖關節(jié)滑膜組織中IRF7、鈣黏附蛋白11(cadherin-11,CDH-11)的蛋白相對表達量均高于股骨頸骨折組和髖骨關節(jié)炎組(P=0.001,P=0.000; P=0.000,P=0.001),髖骨關節(jié)炎組髖關節(jié)滑膜組織中IRF7、CDH-11的蛋白相對表達量高于股骨頸骨折組(P=0.001,P=0.000)。滑膜成纖維細胞為SONFH滑膜病變的靶細胞。⑤細胞驗證結果。模型細胞組IRF4、IRF7、IFN-α的mRNA和蛋白相對表達量均高于空白細胞組(P=0.001,P=0.002,P=0.000; P=0.001,P=0.007,P=0.000)。結論:SONFH滑膜病變與免疫炎癥反應關系密切,滑膜成纖維細胞可能是SONFH滑膜病變的靶細胞,IRF4和IRF7可能是其潛在的靶點。
Abstract:
Objective:To investigate the molecular mechanisms of synovial lesions in steroid-induced osteonecrosis of the femoral head(SONFH).Methods:①RNA sequencing(RNA-seq)and bioinformatics analysis.The hip synovial tissues were collected from patients with SONFH(3 ones),hip osteoarthritis(HOA)(3 ones)and femoral neck fracture(FNF)(3 ones),respectively,during the total hip arthroplasty for RNA-seq and bioinformatics analysis to screen the core genes of synovial lesions in SONFH.②Synovial tissues detection.The hip synovial tissue specimens were divided into SONFH group,HOA group,and FNF group based on their sources,and then were sectioned and stained with hematoxylin-eosin(HE)for observing the morphology.Furthermore,the relative mRNA expression levels of core genes of SONFH-triggered synovial lesions in the hip synovial tissues were detected by using real-time quantitative PCR(RT-qPCR),and the relative protein expression levels of core genes of SONFH-triggered synovial lesions in the hip synovial tissues were detected by employing Western blotting and immunohistochemical staining,respectively.Additionally,the target cells of SONFH-triggered synovial lesions were detected by immunofluorescence staining.③Cell validation.The rat synovial fibroblasts(SFs)were cultured to construct a synovitis-cell model,and the expression of core genes of SONFH-triggered synovial lesions in blank cells(blank cell group)and synovitis model cells(model cell group)were detected by using RT-qPCR and Western blotting,respectively.Results:①The results of RNA-seq and bioinformatics analysis.One thousand and one SONFH-triggered hip synovial lesions-associated genes were screened out by analysis on differentially expressed genes(DEGs)in hip synovial tissues from different patients,and they were all related to immune response and exosomes,with interferon regulatory factor(IRF)4 and IRF7 identified as the core genes for SONFH-triggered hip synovial lesions,both of which were the key transcription factors in participating in type I interferon responses.②The results of observation on morphology of synovial tissues.The result of HE staining showed that,in FNF group,the hip synovial tissues presented with a normal morphology,without cell proliferation,hypertrophy,or interstitial edema; the hip synovial tissues in HOA group exhibited cell proliferation,with a small amount of neovascularization and cell aggregation; while the marked changes,manifesting as a significant increase in cell proliferation and aggregation,with the neovascularization,were observed in hip synovial tissues of SONFH group.③The results of detection on the expression of core genes of SONFH-triggered synovial lesions in synovial tissues.The relative mRNA expression levels of IRF4,IRF7 and interferon-α(IFN-α)in hip synovial tissues were higher in SONFH group compared to FNF group and HOA group(P=0.000,P=0.000,P=0.000; P=0.001,P=0.000,P=0.036),and were higher in HOA group compared to FNF group(P=0.000,P=0.000,P=0.000).The IRF4,IRF7 and IFN-α proteins were highly expressed in the hip synovial tissues in SONFH group.The relative protein expression levels of IRF4,IRF7 and IFN-α in hip synovial tissues were higher in SONFH group compared to FNF group and HOA group(P=0.001,P=0.000,P=0.000; P=0.000,P=0.014,P=0.000),and were higher in HOA group compared to FNF group(P=0.002,P=0.005,P=0.000).④The results of detection on target cells of SONFH-triggered synovial lesions.The relative protein expression levels of IRF7 and cadherin-11(CDH-11)in hip synovial tissues were higher in SONFH group compared to FNF group and HOA group(P=0.001,P=0.000; P=0.000,P=0.001),and were higher in HOA group compared to FNF group(P=0.001,P=0.000).The SFs were identified as the target cells of SONFH-triggered synovial lesions.⑤The results of cell verification.The relative mRNA and protein expression levels of IRF4,IRF7,and IFN-α were higher in model cell group compared to blank cell group(P=0.001,P=0.002,P=0.000; P=0.001,P=0.007,P=0.000).Conclusion:The synovial lesions are closely related to immune-inflammatory responses in patients with SONFH.The SFs may be the target cells of SONFH-triggered synovial lesions,with IRF4 and IRF7 as its potential targets.

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備注/Memo

備注/Memo:
基金項目:國家自然科學基金項目(82274544,82004392); 廣東省基礎與應用基礎研究基金項目(2023A1515010551); 國家中醫(yī)藥管理局高水平中醫(yī)藥重點學科建設項目(zyyzdxk-2023106); 福建中醫(yī)藥大學中醫(yī)骨傷科學學科開放課題資助項目(XGS2023008); 畢節(jié)市科學技術局2022年度“揭榜掛帥”項目(畢科合重大專項〔2022〕1號); 廣東省中醫(yī)骨傷研究院開放課題重點項目(GYH202101-01,GYH202101-04)
通訊作者:何敏聰 E-mail:[email protected]
更新日期/Last Update: 1900-01-01