Background: Osteoclasts are multinucleated cells of myeloid origin with an essential role in skeletal homeostasis due to their unique ability to resorb bone, which act in conjunction with osteoanabolic cells such as osteoblasts and osteocytes. Cellular polarization or differentiation of immune cells is accompanied by metabolic adaptations which reflect changed energetic requirements for novel cellular functions.

Objectives: Previous work on the metabolic regulation of osteoclastogenesis has focused on the terminal differentiation process, however, changes in cellular metabolism during early osteoclastogenesis and whether they are involved in maintaining bone homeostasis are poorly understood.

Methods: We metabolically and transcriptionally profiled cells during osteoclast and osteoblast generation. Individual gene expression was characterized by qPCR and Western blot. Osteoblast function was assessed by Alizarin red staining. K/BxN arthritis and hTNFtg arthritis as well as ovariectomy induced bone loss was performed in Irg1 deficient mice and analyzed clinically and histologically. Tissue gene expression was analysed by RNA in situ hybridization.

Results: 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 generation in vitro and in vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation in both human and murine cells. This enhanced osteogenic differentiation is accompanied by reduced proliferation and altered metabolism. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely, Irg1 deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis.

Conclusion: Our study demonstrates that itaconate is induced during osteoclast generation and identifies a role of itaconate in the regulation of bone biology by stimulating osteogenic differentiation.

REFERENCES: NIL.

Acknowledgements: We thank George Kollias for providing the hTNFtg/+ mice.

Disclosure of Interests: None declared.