Itaconate mediates a metabolic crosstalk between osteoclasts and osteoblasts

Bone remodeling is a highly dynamic process dependent on the precise coordination of osteoblasts and hematopoietic-cell derived osteoclasts. Emerging evidence indicates that cellular differentiation is associated with a metabolic rewiring in conjunction with the acquisition of specific effector functions. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis. We show that during differentiation preosteoclasts rearrange their tricarboxylic acid (TCA) cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterized by induction of immunoresponsive gene 1 (Irg1) and production of itaconate, which accumulates intra- and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generationin vitroandin vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation, reducing proliferation and shifting ATP production from mitochondrial respiration to glycolysis. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely,Irg1deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis. In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognized regulator of the crosstalk between osteoclasts and osteoblasts