Targeting DDX6 attenuates osteoarthritis progression by inhibiting CPEB1-mediated ferroptosis in subchondral bone

Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by the deterioration of articular cartilage, leading to pain and joint stiffness. Ferroptosis is involved in the progression of OA and plays a pivotal role in its pathogenesis. The study aimed to investigate the mechanism by which DEAD-box helicase 6 (DDX6) regulates ferroptosis by interacting with cytoplasmic polyadenylation element-binding protein 1 (CPEB1) and contributes to OA progression by regulating osteosclerosis and microangiogenesis.

Ferroptosis in the subchondral bone and the interaction between DDX6 and CPEB1 in OA osteoblasts were examined in vitro. Expression levels of proteins associated with ferroptosis, osteosclerosis, and H-type microangiogenesis were measured following DDX6 and CPEB1 overexpression or knockdown using lentiviral and small-interfering RNA transfection. In vivo, we used 10-week-old mice with osteoblast-specific conditional knockout of Ddx6 (Ddx6fl/fl OC-Cre+) and intra-articular injection of ferrostatin-1 in a destabilization of the medial meniscus-induced OA model to evaluate effects on cartilage degeneration, microangiogenic activity, and subchondral bone microarchitecture.

Ferroptosis in OA osteoblasts, driven by mitochondrial dysfunction and the DDX6-CPEB1 interaction, was confirmed. Both DDX6 and CPEB1 were upregulated in subchondral bone of patients with OA and model mice. Upregulation or downregulation of DDX6 and CPEB1 levels led to corresponding changes in the expression of downstream H-type microangiogenesis-related proteins (vascular endothelial growth factor, hypoxia-inducible factor 1 alpha, cluster of differentiation 31, and endomucin), bone osteosclerosis-related proteins (osteocalcin [OCN], runt-related transcription factor 2 [RUNX2] and glutathione peroxidase 4 [GPX4]). These alterations ultimately affected chondrocyte metabolism through the bone-cartilage functional unit. Conditional knockout of Ddx6 reduced subchondral microvascular infiltration and alleviated cartilage destruction, whereas intra-articular ferrostatin-1 injection showed even greater protective effects.

DDX6 promotes OA progression by regulating ferroptosis through interaction with CPEB1, which in turn influences H-type microangiogenesis and osteosclerosis. Targeting DDX6 may represent a promising therapeutic strategy for OA.