Anti-MDA antibodies are inducers of osteoclast maturation and bone erosion in RA.

Anti-MDA antibodies boost glycolysis via FcγRI, HIF-1α and MYC in pre-osteoclast.

Osteoclast glycolysis fuels mitochondrial oxidation and overproduction of citrate.

Anti-MDA boosts lipid biosynthesis via regulating citrate and the GPD1/GPAT2 genes.

Glycerolipid biosynthesis is crucial for osteoclast development.

Proteins subjected to post-translational modifications, such as citrullination, carbamylation, acetylation or malondialdehyde (MDA)-modification are targeted by autoantibodies in seropositive rheumatoid arthritis (RA). Epidemiological and experimental studies have both suggested the pathogenicity of such humoral autoimmunity, however, molecular mechanisms triggered by anti-modified protein antibodies have remained to be identified.

Here we describe in detail the pathways induced by anti-MDA modified protein antibodies that were obtained from synovial B cells of RA patients and that possessed robust osteoclast stimulatory potential and induced bone erosion in vivo. Anti-MDA antibodies boosted glycolysis in developing osteoclasts via an FcγRI, HIF-1α and MYC-dependent mechanism and subsequently increased oxidative phosphorylation. Osteoclast development required robust phosphoglyceride and triacylglyceride biosynthesis, which was also enhanced by anti-MDA by modulating citrate production and expression of the glycerol-3-phosphate dehydrogenase 1 (GPD1) and glycerol-3-phosphate acyltransferase 2 (GPAT2) genes. In summary, we described novel metabolic pathways instrumental for osteoclast differentiation, which were targeted by anti-MDA antibodies, accelerating bone erosion, a central component of RA pathogenesis.

Rheumatoid arthritis

Osteoclast

Autoantibody

Glycolysis

Lipid biosynthesis

Anti-MDA modified protein antibody

© 2022 The Authors. Published by Elsevier Ltd.