Protein folding dependence on Selenoprotein M contributes to steady cartilage extracellular matrix repressing ferroptosis specifically access to PERK/ATF4/CHAC1 axis
Oateoarthritis (OA) commonly attends persistent inflammatory injury, extensive cartilage structural destruction and severe extracellular matrix (ECM) degradation. This study provides an overview of decreasing endoplasmic reticulum (ER)-resident selenoprotein M (SELM) probed into OA cartilage. Overexpression of SELM in chondrocytes positively promoted the synthesis of ECM. RNA-Seq results represented the mobilization of genes touched on various parts of degenerative diseases, inflammation and ferroptosis after SELM knockdown, which also negatively regulated cellular response to misfolded proteins and led to the activation of ER stress mediated by the PERK/P-EIF2A/ATF4 pathway in chondrocytes. Protein docking results captured that SELM was overwhelmingly likely to be involved in protein disulfide bond formation and modification processes by interacting with PDI, GRP94, CNX and CRT, resting on its thioredoxin domain. Decreased SELM also deepened GSH/GSSG homeostasis imbalance through the ATF4/CHAC1 axis and sparking ferroptosis. In vitro supplementation of SELM was buffering the effects of IL-1ß on tattered cartilage explants. Furthermore, SELM also powered up the maintenance of favorable proliferative and homeostatic phenotypes among to an inhibitory effect on the hypertrophic phenotype in chondrocytes. These results make conclusive proof to unravel the involvement of SELM in ER stress induced cartilage damage and depict the distinctive function of SELM in protein folding, which renews directions for molecular therapeutic of degenerative diseases. Overall design: Primary chondrocytes derived from three different patients' smooth cartilage sites were divided into two groups and subjected to treatment with Selenoprotein M-specifically siRNA or adenovirus for a duration of 24 hours. Following stimulation, the total RNA was extracted and transferred for transcriptome sequencing by Sangong Biotech (Shanghai, China).