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Abstract
Objectives Metabolic changes are crucially involved in osteoclast development and may contribute to bone degradation in rheumatoid arthritis (RA). The enzyme aconitate decarboxylase 1 (Acod1) is known to link the cellular function of monocyte-derived macrophages to their metabolic status. As osteoclasts derive from the monocyte lineage, we hypothesised a role for Acod1 and its metabolite itaconate in osteoclast differentiation and arthritis-associated bone loss.
Methods Itaconate levels were measured in human peripheral blood mononuclear cells (PBMCs) of patients with RA and healthy controls by mass spectrometry. Human and murine osteoclasts were treated with the itaconate derivative 4-octyl-itaconate (4-OI) in vitro. We examined the impact of Acod1-deficiency and 4-OI treatment on bone erosion in mice using K/BxN serum-induced arthritis and human TNF transgenic (hTNFtg) mice. SCENITH and extracellular flux analyses were used to evaluate the metabolic activity of osteoclasts and osteoclast progenitors. Acod1-dependent and itaconate-dependent changes in the osteoclast transcriptome were identified by RNA sequencing. CRISPR/Cas9 gene editing was used to investigate the role of hypoxia-inducible factor (Hif)-1α in Acod1-mediated regulation of osteoclast development.
Results Itaconate levels in PBMCs from patients with RA were inversely correlated with disease activity. Acod1-deficient mice exhibited increased osteoclast numbers and bone erosion in experimental arthritis while 4-OI treatment alleviated inflammatory bone loss in vivo and inhibited human and murine osteoclast differentiation in vitro. Mechanistically, Acod1 suppressed osteoclast differentiation by inhibiting succinate dehydrogenase-dependent production of reactive oxygen species and Hif1α-mediated induction of aerobic glycolysis.
Conclusion Acod1 and itaconate are crucial regulators of osteoclast differentiation and bone loss in inflammatory arthritis.
- Bone Density
- Arthritis, Experimental
- Arthritis, Rheumatoid
- Inflammation
- Osteoporosis
Data availability statement
Data are available on reasonable request. All sequencing data have been deposited in the National Centre for Biotechnology Information Gene Expression Omnibus (GEO). The accession number for the sequencing data reported in this paper is GEO: GSE237504.
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Data availability statement
Data are available on reasonable request. All sequencing data have been deposited in the National Centre for Biotechnology Information Gene Expression Omnibus (GEO). The accession number for the sequencing data reported in this paper is GEO: GSE237504.
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Footnotes
Handling editor Rik Jozef Urbain Lories
Contributors KK acquired funding, designed the study, performed experiments, interpreted results and wrote the manuscript. DA, ST, SK, MLP and ML performed experiments, collected and interpreted data. DR and AS provided expertise and helped to establish the CRISPR/ Cas9-mediated gene knockout experiments. JH, AG and MF provided expertise and performed mass spectrometry analyses. SR helped to establish the hTNFtg arthritis model. XM helped to establish the SCENITH experiments. AG performed transmission electron microscopy analyses. GS and AB acquired funding, directed the study and wrote the manuscript. AB is responsible for the overall content as guarantor. All authors read and commented on the manuscript.
Funding This study was supported by the Interdisciplinary Center for Clinical Research (IZKF) grant J76, J90 and A77, the Collaborative Research Centre 1181 project A01, the Collaborative Research Center/Transregio 369 project B03, the German Research Foundation grant FOR2886 TP02, TRR/CRC369 DIONE—501752319 project A02, INST90/1048-1 FUGG, GRK2599-FAIR and GRK2740-immunomocrotope, the European Research Council Consolidator Grant LS4-ODE, the Leibniz Award of the DFG (to GS) and the Synergy Grant 4D Nanoscope.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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