Metabolic rewiring controlled by c-Fos governs cartilage integrity in osteoarthritis
Kazuhiko Matsuoka, Latifa Bakiri, Martin Bilban, Stefan Toegel, Arvand Haschemi, Hao Yuan, Maria Kasper, Reinhard Windhager, Erwin F. Wagner
Abstract
<h3>Objectives</h3> The 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. <h3>Methods</h3> c-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<sup>ΔCh</sup>) mice were generated by crossing <i>c-fos<sup>fl/fl</sup></i> to <i>Col2a1-CreERT</i> mice. Articular cartilage was evaluated by histology, immunohistochemistry, RNA sequencing (RNA-seq), quantitative reverse transcription PCR (qRT-PCR) and <i>in situ</i> metabolic enzyme assays. The effect of dichloroacetic acid (DCA), an inhibitor of pyruvate dehydrogenase kinase (Pdk), was assessed in c-Fos<sup>ΔCh</sup> mice subjected to DMM. <h3>Results</h3> FOS-positive chondrocytes were increased in human and murine OA cartilage during disease progression. Compared with c-Fos<sup>WT</sup> mice, c-Fos<sup>ΔCh</sup> 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 <i>in situ</i>, which are likely due to higher expression of hypoxia-inducible factor-1α, <i>Ldha</i>, and Pdk1 in chondrocytes. <i>In vivo</i> treatment of c-Fos<sup>ΔCh</sup> 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. <h3>Conclusions</h3> c-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.