Itaconate is a metabolic regulator of bone formation in homeostasis and arthritis Journal Article
| Authors: | Kieler, M.; Prammer, L. S.; Heller, G.; Hofmann, M.; Sperger, S.; Hanetseder, D.; Niederreiter, B.; Komljenovic, A.; Klavins, K.; Köcher, T.; Brunner, J. S.; Stanic, I.; Oberbichler, L.; Korosec, A.; Vogel, A.; Kerndl, M.; Hromadová, D.; Musiejovsky, L.; Hajto, A.; Dobrijevic, A.; Piwonka, T.; Haschemi, A.; Miller, A.; Georgel, P.; Presen, D. M.; Grillari, J.; Hayer, S.; Auger, J. P.; Krönke, G.; Sharif, O.; Aletaha, D.; Schabbauer, G.; Blüml, S. |
| Article Title: | Itaconate is a metabolic regulator of bone formation in homeostasis and arthritis |
| Abstract: | Objectives Bone remodelling is a highly dynamic process dependent on the precise coordination of osteoblasts and haematopoietic-cell derived osteoclasts. 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. Methods We metabolically and transcriptionally profiled cells during osteoclast and osteoblast generation. Individual gene expression was characterised by quantitative PCR and western blot. Osteoblast function was assessed by Alizarin red staining. immunoresponsive gene 1 (Irg1)-deficient mice were used in various inflammatory or non-inflammatory models of bone loss. Tissue gene expression was analysed by RNA in situ hybridisation. Results We show that during differentiation preosteoclasts rearrange their tricarboxylic acid cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterised by the induction of Irg1 and production of itaconate, which accumulates intracellularly 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 In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognised regulator of osteoblasts. © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ. |
| Keywords: | controlled study; osteolysis; human cell; nonhuman; flow cytometry; animal cell; mouse; animal; metabolism; animals; mice; mice, knockout; animal tissue; gene; gene expression; animal experiment; animal model; inflammation; immunoglobulin enhancer binding protein; cell differentiation; drug effect; pathology; enzyme activity; enzyme linked immunosorbent assay; histology; bone density; physiology; in situ hybridization; alkaline phosphatase; arthritis; western blotting; glucose; real time polymerase chain reaction; ossification; osteoclast; bone development; osteoclasts; osteogenesis; homeostasis; bone marrow transplantation; bone remodeling; oxidative phosphorylation; flow rate; knockout mouse; osteoblast; osteoblasts; osteoclastogenesis; osteoclast differentiation factor; citric acid cycle; metabolomics; carbon 13; liquid chromatography-mass spectrometry; experimental; carboxylyase; isotope tracing; glycoprotein p 15095; humans; human; female; article; ultra performance liquid chromatography; succinic acid derivative; carboxy-lyases; hydro-lyases; gene set enrichment analysis; morphometry; hydrophilic interaction chromatography; arthritis, experimental; hydrolyase; itaconic acid; mrna expression level; grip strength test; experimental arthritis; actb gene; ankylosing; spondylitis; succinates; acod1 protein, human; acod1 protein, mouse; gapdh gene; irg1 gene |
| Journal Title: | Annals of the Rheumatic Diseases |
| Volume: | 83 |
| Issue: | 11 |
| ISSN: | 0003-4967 |
| Publisher: | BMJ Publishing Group Ltd. |
| Date Published: | 2024-11-01 |
| Start Page: | 1465 |
| End Page: | 1479 |
| Language: | English |
| DOI: | 10.1136/ard-2023-224898 |
| PUBMED: | 38986577 |
| PROVIDER: | scopus |
| PMCID: | PMC11503170 |
| DOI/URL: | |
| Notes: | Source: Scopus |
