{"title":"缺乏软骨特异性Y-box结合蛋白1可抑制NF-κB信号传导并缓解骨关节炎的进展。","authors":"Xinyu Li,Zhao Zhang,Jinwei Xie,Weihua Guo,Zhenhan Deng,Zeyu Huang","doi":"10.1002/art.43311","DOIUrl":null,"url":null,"abstract":"OBJECTIVE\r\nTo explore the role of Y-box binding protein 1 (YBX1) in the pathogenesis of osteoarthritis (OA).\r\n\r\nMETHODS\r\nThe proteome and phosphoproteome were compared between the intact and osteoarthritic regions of the cartilage from patients undergoing total knee arthroplasty, establishing a connection between the pathology and YBX1 upregulation. Normal C57BL/6 and cartilage-specific Ybx1-deficient mice underwent medial meniscal destabilization surgery; the behavior, micro-computed tomography, and histology were compared. YBX1 was overexpressed in the C28/I2 cell line, and potential binding partners were identified using immunoprecipitation and mass spectrometry. MedChemExpress drug libraries were screened for potential small-molecule inhibitors of YBX1, and candidates were injected intra-articularly into a mouse OA model.\r\n\r\nRESULTS\r\nThe total YBX1 and YBX1 phosphorylated levels at S102 were higher in the osteoarthritic than intact human cartilage. Ybx1 knockout in chondrocytes alleviated disease progression in an OA mouse model. Upregulation of YBX1 in chondrocytes activated NF-κB signaling. Phosphorylation of YBX1 at S102 promoted its entry into the nucleus, where it inhibited NF-κB-repressing factor (NKRF), upregulating target genes of NF-κB. Virtual drug screening identified hesperidin methychalcone and mulberroside A as candidates for inhibiting S102 phosphorylation, alleviating disease progression in an injury-induced OA mouse model.\r\n\r\nCONCLUSION\r\nYBX1 contributes to OA progression by inhibiting NKRF, activating NF-κB signaling; therefore targeting YBX1 is a potential therapeutic strategy for the treatment of OA.","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"9 1","pages":""},"PeriodicalIF":10.9000,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Deficiency of cartilage-specific Y-box binding protein 1 represses NF-κB signaling and alleviates osteoarthritis progression.\",\"authors\":\"Xinyu Li,Zhao Zhang,Jinwei Xie,Weihua Guo,Zhenhan Deng,Zeyu Huang\",\"doi\":\"10.1002/art.43311\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"OBJECTIVE\\r\\nTo explore the role of Y-box binding protein 1 (YBX1) in the pathogenesis of osteoarthritis (OA).\\r\\n\\r\\nMETHODS\\r\\nThe proteome and phosphoproteome were compared between the intact and osteoarthritic regions of the cartilage from patients undergoing total knee arthroplasty, establishing a connection between the pathology and YBX1 upregulation. Normal C57BL/6 and cartilage-specific Ybx1-deficient mice underwent medial meniscal destabilization surgery; the behavior, micro-computed tomography, and histology were compared. YBX1 was overexpressed in the C28/I2 cell line, and potential binding partners were identified using immunoprecipitation and mass spectrometry. MedChemExpress drug libraries were screened for potential small-molecule inhibitors of YBX1, and candidates were injected intra-articularly into a mouse OA model.\\r\\n\\r\\nRESULTS\\r\\nThe total YBX1 and YBX1 phosphorylated levels at S102 were higher in the osteoarthritic than intact human cartilage. Ybx1 knockout in chondrocytes alleviated disease progression in an OA mouse model. Upregulation of YBX1 in chondrocytes activated NF-κB signaling. Phosphorylation of YBX1 at S102 promoted its entry into the nucleus, where it inhibited NF-κB-repressing factor (NKRF), upregulating target genes of NF-κB. Virtual drug screening identified hesperidin methychalcone and mulberroside A as candidates for inhibiting S102 phosphorylation, alleviating disease progression in an injury-induced OA mouse model.\\r\\n\\r\\nCONCLUSION\\r\\nYBX1 contributes to OA progression by inhibiting NKRF, activating NF-κB signaling; therefore targeting YBX1 is a potential therapeutic strategy for the treatment of OA.\",\"PeriodicalId\":129,\"journal\":{\"name\":\"Arthritis & Rheumatology\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":10.9000,\"publicationDate\":\"2025-07-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Arthritis & Rheumatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/art.43311\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arthritis & Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/art.43311","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
Deficiency of cartilage-specific Y-box binding protein 1 represses NF-κB signaling and alleviates osteoarthritis progression.
OBJECTIVE
To explore the role of Y-box binding protein 1 (YBX1) in the pathogenesis of osteoarthritis (OA).
METHODS
The proteome and phosphoproteome were compared between the intact and osteoarthritic regions of the cartilage from patients undergoing total knee arthroplasty, establishing a connection between the pathology and YBX1 upregulation. Normal C57BL/6 and cartilage-specific Ybx1-deficient mice underwent medial meniscal destabilization surgery; the behavior, micro-computed tomography, and histology were compared. YBX1 was overexpressed in the C28/I2 cell line, and potential binding partners were identified using immunoprecipitation and mass spectrometry. MedChemExpress drug libraries were screened for potential small-molecule inhibitors of YBX1, and candidates were injected intra-articularly into a mouse OA model.
RESULTS
The total YBX1 and YBX1 phosphorylated levels at S102 were higher in the osteoarthritic than intact human cartilage. Ybx1 knockout in chondrocytes alleviated disease progression in an OA mouse model. Upregulation of YBX1 in chondrocytes activated NF-κB signaling. Phosphorylation of YBX1 at S102 promoted its entry into the nucleus, where it inhibited NF-κB-repressing factor (NKRF), upregulating target genes of NF-κB. Virtual drug screening identified hesperidin methychalcone and mulberroside A as candidates for inhibiting S102 phosphorylation, alleviating disease progression in an injury-induced OA mouse model.
CONCLUSION
YBX1 contributes to OA progression by inhibiting NKRF, activating NF-κB signaling; therefore targeting YBX1 is a potential therapeutic strategy for the treatment of OA.
期刊介绍:
Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.