Li Xinyu, Zhang Zhao, Xie Jinwei, Guo Weihua, Deng Zhenhan, Huang Zeyu
Department of Orthopaedic Surgery, Orthopaedic Research Institute, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, People's Republic of China.
Department of Immuno-oncology, City of Hope, National Medical Center, Duarte, California, USA.
Arthritis Rheumatol. 2025 Jul 14. doi: 10.1002/art.43311.
To explore the role of Y-box binding protein 1 (YBX1) in the pathogenesis of osteoarthritis (OA).
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.
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.
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.
探讨Y盒结合蛋白1（YBX1）在骨关节炎（OA）发病机制中的作用。
比较接受全膝关节置换术患者软骨完整区域与骨关节炎区域的蛋白质组和磷酸化蛋白质组，建立病理学与YBX1上调之间的联系。对正常C57BL/6小鼠和软骨特异性Ybx1基因敲除小鼠进行内侧半月板失稳手术；比较其行为、显微计算机断层扫描和组织学情况。在C28/I2细胞系中过表达YBX1，通过免疫沉淀和质谱鉴定潜在的结合伴侣。筛选MedChemExpress药物库中YBX1的潜在小分子抑制剂，并将候选药物关节腔内注射到小鼠OA模型中。
骨关节炎患者软骨中总YBX1及S10位点磷酸化YBX1水平高于正常软骨。软骨细胞中Ybx1基因敲除可减轻OA小鼠模型的疾病进展。软骨细胞中YBX1上调激活NF-κB信号通路。YBX1在S102位点的磷酸化促进其进入细胞核，在细胞核中它抑制NF-κB抑制因子（NKRF），上调NF-κB的靶基因。虚拟药物筛选确定橙皮素甲基查耳酮和桑色素苷A为抑制S102磷酸化的候选药物，可减轻损伤诱导的OA小鼠模型的疾病进展。
YBX1通过抑制NKRF、激活NF-κB信号通路促进OA进展；因此，靶向YBX1是治疗OA的一种潜在治疗策略。
