OBJECTIVE Initiation of endoplasmic reticulum (ER) stress is pivotal to the advancement of osteoarthritis (OA). We aimed to explore the function of ER-resident selenoprotein M (SELM) in cartilage-forming chondrocytes, investigating how SELM participates in cartilage extracellular matrix (ECM) metabolism and ER stress modulation. METHODS Articular cartilage samples with knee OA undergoing total knee arthroplasty were categorised into OA-smooth and OA-damaged groups, with primary chondrocytes extracted from smooth areas. Destabilization of the medial meniscus was induced in male C57BL6/J mice, with sham operations on the left knee as controls. After 8 weeks, knee joint tissues were collected for analysis. Histology and immunohistochemistry examined cartilage damage. Molecular biology techniques investigated how SELM affects ECM metabolism and ER stress regulation. RNA sequencing revealed the pathway changes after SELM intervention. AlphaFold demonstrated how SELM interacts with other molecules. Cultured cartilage explants helped determine the effects of SELM supplementation. RESULTS SELM expression was reduced in the damaged cartilage. Increasing SELM levels positively impacted ECM equilibrium. Decreasing SELM expression activated genes linked to degenerative ailments and impaired the cellular response to misfolded proteins, initiating the PERK/P-EIF2A/ATF4 pathway and exacerbating GSH/GSSG imbalance via the ATF4/CHAC1 axis. SELM likely participated in protein folding and modification by leveraging its thioredoxin domains. In vitro SELM supplementation mitigated IL-1β effects on damaged cartilage explants and suppressed beneficial chondrocyte phenotypes. CONCLUSIONS Our results confirm the involvement of SELM in ER stress-induced cartilage damage as well as protein folding, pointing to new directions in molecular therapy for degenerative diseases.

中文翻译：

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蛋白质折叠对硒蛋白 M 的依赖性有助于稳定的软骨细胞外基质通过 PERK/ATF4/CHAC1 轴抑制铁死亡。


目的 内质网 （ER） 应激的开始对骨关节炎 （OA） 的进展至关重要。我们旨在探索 ER 驻留硒蛋白 M （SELM） 在软骨形成软骨细胞中的功能，研究 SELM 如何参与软骨细胞外基质 （ECM） 代谢和 ER 应激调节。方法 将接受全膝关节置换术的膝关节 OA 关节软骨样本分为 OA 平滑组和 OA 损伤组，原代软骨细胞从光滑区域提取。雄性 C57BL6/J 小鼠诱导内侧半月板不稳定，左膝假手术作为对照。8 周后，收集膝关节组织进行分析。组织学和免疫组化检查软骨损伤。分子生物学技术研究了 SELM 如何影响 ECM 代谢和 ER 应激调节。RNA 测序揭示了 SELM 干预后的通路变化。AlphaFold 演示了 SELM 如何与其他分子相互作用。培养的软骨外植体有助于确定 SELM 补充剂的效果。结果 SELM 在受损软骨中的表达降低。增加 SELM 水平对 ECM 平衡产生积极影响。降低 SELM 表达激活了与退行性疾病相关的基因，并损害了细胞对错误折叠蛋白质的反应，启动 PERK/P-EIF2A/ATF4 通路并通过 ATF4/CHAC1 轴加剧了 GSH/GSSG 失衡。SELM 可能通过利用其硫氧还蛋白结构域参与了蛋白质折叠和修饰。体外 SELM 补充剂减轻了 IL-1β 对受损软骨外植体的影响，并抑制了有益的软骨细胞表型。 结论 我们的结果证实了 SELM 参与 ER 应力诱导的软骨损伤以及蛋白质折叠，为退行性疾病的分子治疗指明了新的方向。