Metabolic rewiring controlled by c-Fos governs cartilage integrity in osteoarthritis

ObjectivesThe activator protein-1 (AP-1) transcription factor component c-Fos regulates chondrocyte proliferation and differentiation, but its involvement in osteoarthritis (OA) has not been functionally assessed. Methodsc-Fos expression was evaluated by immunohistochemistry on articular cartilage sections from patients with OA and mice subjected to the destabilisation of the medial meniscus (DMM) model of OA. Cartilage-specific c-Fos knockout (c-Fos(& UDelta;Ch)) mice were generated by crossing c-fos(fl/fl) to Col2a1-CreERT mice. Articular cartilage was evaluated by histology, immunohistochemistry, RNA sequencing (RNA-seq), quantitative reverse transcription PCR (qRT-PCR) and in situ metabolic enzyme assays. The effect of dichloroacetic acid (DCA), an inhibitor of pyruvate dehydrogenase kinase (Pdk), was assessed in c-Fos(& UDelta;Ch) mice subjected to DMM. ResultsFOS-positive chondrocytes were increased in human and murine OA cartilage during disease progression. Compared with c-Fos(WT) mice, c-Fos(& UDelta;Ch) mice exhibited exacerbated DMM-induced cartilage destruction. Chondrocytes lacking c-Fos proliferate less, have shorter collagen fibres and reduced cartilage matrix. Comparative RNA-seq revealed a prominent anaerobic glycolysis gene expression signature. Consistently decreased pyruvate dehydrogenase (Pdh) and elevated lactate dehydrogenase (Ldh) enzymatic activities were measured in situ, which are likely due to higher expression of hypoxia-inducible factor-1 & alpha;, Ldha, and Pdk1 in chondrocytes. In vivo treatment of c-Fos(& UDelta;Ch) mice with DCA restored Pdh/Ldh activity, chondrocyte proliferation, collagen biosynthesis and decreased cartilage damage after DMM, thereby reverting the deleterious effects of c-Fos inactivation. Conclusionsc-Fos modulates cellular bioenergetics in chondrocytes by balancing pyruvate flux between anaerobic glycolysis and the tricarboxylic acid cycle in response to OA signals. We identify a novel metabolic adaptation of chondrocytes controlled by c-Fos-containing AP-1 dimers that could be therapeutically relevant.

Automated summary

This study assessed the involvement of the c-Fos protein in osteoarthritis (OA) and its role in chondrocyte proliferation and differentiation. The expression of c-Fos was analyzed in human and murine OA cartilage. Cartilage-specific c-Fos knockout mice were generated and evaluated for cartilage damage and metabolic enzyme activity. Treatment with dichloroacetic acid (DCA) was used to restore the deleterious effects of c-Fos inactivation.