Mitochondrial serine metabolism fuels epigenetic remodelling in osteoclast differentiation and is the main target of methotrexate

Osteoclasts are specialized myeloid cells with crucial roles in skeletal homeostasis and disease. Differentiation of precursor cells to osteoclasts requires extensive metabolic and epigenetic rewiring, but pathways governing these processes are poorly characterized. Here, we found that transdifferentiation into osteoclasts crucially depends on the generation of one carbon units from serine catabolized by SHMT2. Serine mediatedde novopurine synthesis fuels increased mitochondrial ATP production and ultimately SAM generation necessary for epigenetic repression of macrophage lineage genes. Intriguingly, methotrexate restrains osteoclast precursors from engaging in serine mediated one carbon metabolism, unravelling a hitherto unknown therapeutic mechanism of action. Supplementation of purine precursor metabolites which restore mitochondrial ATP generation fully rescues osteoclastogenesis of SHMT2 knockout or methotrexate inhibited cells. Together, we show an essential role of serine catabolism for metabolic epigenetic coupling in osteoclast differentiation and provide a framework how methotrexate prevents osteoclast-mediated joint destruction.