Frontiers in immunology · 2026
TEFM drives cartilage degeneration in osteoarthritis via the ROS-AKT/NF-κB signaling axis.
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Yang Kanghua, Lu Meifeng, Xiao Runting, Xu Shuai, Ouyang Yulong, Sun Guicai
Аннотация
OBJECTIVE: To explore the role and underlying mechanism of mitochondrial transcription elongation factor TEFM in osteoarthritis (OA) cartilage degeneration.
METHODS: Bioinformatics analysis based on the GSE114007 human knee cartilage dataset and two-sample Mendelian randomization (MR) analysis were performed to evaluate the association between TEFM and knee OA. Human cartilage specimens were collected to verify TEFM expression patterns. Lentivirus-mediated TEFM knockdown was performed in ATDC5 chondrocytes, and an in vitro inflammatory injury model was established by interleukin-1β (IL-1β) stimulation. The effects of TEFM on chondrocyte function were determined by RT-qPCR, Western blotting, toluidine blue staining, and immunofluorescence staining. Transcriptome sequencing (RNA-seq), reactive oxygen species (ROS) scavenging, specific pathway inhibition, and H2O2 rescue assays were employed to elucidate TEFM-mediated signaling cascades. For in vivo validation, a destabilization of the medial meniscus (DMM)-induced OA mouse model was established, and adeno-associated virus serotype 9 carrying sh-TEFM (AAV9-sh-TEFM) was administered via intra-articular injection. Pathological changes in cartilage and subchondral bone were assessed by micro-CT and histological staining.
RESULTS: TEFM expression was significantly upregulated in OA cartilage, and MR analysis supported a potential causal association with knee OA risk. In vitro experiments demonstrated that TEFM knockdown ameliorated chondrocyte dysfunction, attenuated mitochondrial oxidative stress, and suppressed AKT/NF-κB pathway activation. Mechanistically, NAC treatment and H2O2 rescue assays verified that ROS serve as a critical upstream mediator linking TEFM to AKT/NF-κB signaling, and specific inhibitor assays further confirmed the functional necessity of the AKT/NF-κB cascade in TEFM-mediated chondrocyte injury. In vivo studies revealed that intra-articular TEFM silencing alleviated cartilage degeneration and subchondral bone pathological damage in OA mice, accompanied by inhibition of the AKT/NF-κB pathway.
CONCLUSION: TEFM facilitates OA cartilage degeneration via the ROS-AKT/NF-κB axis, which provides a novel therapeutic target for OA.
METHODS: Bioinformatics analysis based on the GSE114007 human knee cartilage dataset and two-sample Mendelian randomization (MR) analysis were performed to evaluate the association between TEFM and knee OA. Human cartilage specimens were collected to verify TEFM expression patterns. Lentivirus-mediated TEFM knockdown was performed in ATDC5 chondrocytes, and an in vitro inflammatory injury model was established by interleukin-1β (IL-1β) stimulation. The effects of TEFM on chondrocyte function were determined by RT-qPCR, Western blotting, toluidine blue staining, and immunofluorescence staining. Transcriptome sequencing (RNA-seq), reactive oxygen species (ROS) scavenging, specific pathway inhibition, and H2O2 rescue assays were employed to elucidate TEFM-mediated signaling cascades. For in vivo validation, a destabilization of the medial meniscus (DMM)-induced OA mouse model was established, and adeno-associated virus serotype 9 carrying sh-TEFM (AAV9-sh-TEFM) was administered via intra-articular injection. Pathological changes in cartilage and subchondral bone were assessed by micro-CT and histological staining.
RESULTS: TEFM expression was significantly upregulated in OA cartilage, and MR analysis supported a potential causal association with knee OA risk. In vitro experiments demonstrated that TEFM knockdown ameliorated chondrocyte dysfunction, attenuated mitochondrial oxidative stress, and suppressed AKT/NF-κB pathway activation. Mechanistically, NAC treatment and H2O2 rescue assays verified that ROS serve as a critical upstream mediator linking TEFM to AKT/NF-κB signaling, and specific inhibitor assays further confirmed the functional necessity of the AKT/NF-κB cascade in TEFM-mediated chondrocyte injury. In vivo studies revealed that intra-articular TEFM silencing alleviated cartilage degeneration and subchondral bone pathological damage in OA mice, accompanied by inhibition of the AKT/NF-κB pathway.
CONCLUSION: TEFM facilitates OA cartilage degeneration via the ROS-AKT/NF-κB axis, which provides a novel therapeutic target for OA.