Background/Purpose: Malondialdehyde (MDA) is highly reactive compound produced by lipid-peroxidation in situations associated with oxidative stress. MDA can irreversibly modify proteins (e.g. lysine, arginine and histidine residues), which can lead to the generation of immunogenic neo-epitopes that are recognized by autoantibodies. In fact, anti-MDA IgG antibodies are significantly increased in the serum of patients with autoimmune diseases, such as rheumatoid arthritis (1). Recently, anti-MDA IgG antibodies have been shown to promote osteoclast (OC) differentiation in vitro (1). In this study, we decided to further elucidate the molecular mechanisms triggered by these autoantibodies during osteoclastogenesis.

Methods: OCs were generated from monocyte-derived macrophages in the presence of the cytokines RANK-L and M-CSF. The development of OCs was monitored by light microscopy following tartrate-resistant acid phosphatase (TRAP) staining. Three different recombinant human monoclonal anti-MDA antibodies, generated by single-cells cloning from synovial RA B cells, or control antibodies were added to OC cultures. Cellular metabolism was monitored using Seahorse XF Analyzer (extracellular acidification rate and oxygen consumption) and a colorimetric L-Lactate assay. Genes expressions were assessed by RT-PCR.

Results: Lactic acid production correlated with stimulatory effect of anti-MDA antibodies on OCs, suggesting an antibody-mediated regulation of glycolysis. Moreover, extracellular acidification rate and oxygen consumption of the developing OCs were increased by the osteoclastogenic anti-MDA clone but not by control antibodies. We have also observed the upregulation of genes encoding the glucose transporter GLUT1 and the down-regulation of the pyruvate dehydrogenase kinase (PDK)2 and PDK4 enzymes by anti-MDA antibodies. The glycolysis inhibitor 2-deoxyglucose eliminated the stimulatory effect of anti-MDA clone on OCs at drug concentrations that did not influence baseline OC development.

Conclusion: Our study further confirmed that IgG autoantibodies against MDA/MDA-acetaldehyde posttranslational modifications might have pathological roles in RA. We showed that certain anti-MDA clones induced an early boost of glycolysis and mitochondrial respiration in developing OCs and these metabolic changes led to an increased OC differentiation. Our study thus described a new type of autoantibody-induced cellular mechanism that can contribute to bone abnormalities.

Reference: (1) C. Grönwall et al. Journal of Autoimmunity 84 (2017) 29-45.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/metabolic-changes-induced-by-anti-malondialdehyde-antibodies-promote-osteoclast-development/