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- Gu, Y, et al.
(författare)
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Quick Hot Shot & Young Surgeon Presentation
- 2015
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Ingår i: Hernia : the journal of hernias and abdominal wall surgery. - 1248-9204. ; 19 Suppl 1, s. S77-84
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Tidskriftsartikel (refereegranskat)
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- Sakuraba, K, et al.
(författare)
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METABOLIC CHANGES INDUCED BY ANTI-MALONDIALDEHYDE/MALINDIALDEHYDE-ACETALDEHYDE ANTIBODIES PROMOTE OSTEOCLAST DEVELOPMENT
- 2020
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 934-935
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Malondialdehyde (MDA) is a highly reactive compound produced by lipid-peroxidation in situations associated with oxidative stress. MDA can irreversibly modify proteins residues such as lysine, arginine and histidine. In addition, MDA adducts can further react with acetaldehyde to generate malondialdehyde-acetaldehyde (MAA) modifications. Such modifications can give rise to immunogenic neo-epitopes that are recognized by autoantibodies. In fact, anti-MDA/MAA IgG antibodies are significantly increased in the serum of patients with autoimmune diseases, such as rheumatoid arthritis (RA) (1) and systemic lupus erythematosus (2). Recently, we have shown that anti-MDA/MAA IgG antibodies are able to promote osteoclast (OC) differentiationin vitro(1).Objectives:To investigate the molecular mechanisms triggered by anti-MDA/MAA 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 and erosion area on synthetic calcium phosphate-coated plates. Three different recombinant human monoclonal anti-MDA/MAA antibodies, cloned from single synovial B cells of RA patients, control antibodies and Fab fragments of the antibodies were added to OC cultures. Glycolysis was inhibited by 2-deoxyglucose, and Fc-gamma receptor I or II by anti-CD64 or anti-CD16 neutralizing antibodies. IL-8 levels were measured by enzyme linked immunosorbent assay. Cellular metabolism was monitored using Seahorse XF Analyzer (extracellular acidification rate and oxygen consumption) and a colorimetric L-Lactate assay.Results:Lactic acid production correlated with the osteoclastogenetic effect of some but not all anti-MDA/MAA antibodies on OCs (R=0.4758, p=0.0252) suggesting an antibody-mediated regulation of glycolysis. Further, extracellular acidification (ECAR) and oxygen consumption (OCR) rate of the developing OCs were increased by the osteoclastogenic anti-MDA/MAA clones (maximum increase of 54% for the ECAR and 78% for the OCR by clone 146+:01G07, and maximum increase of 28% for the ECAR and 39% for the OCR by clone 1103:01H05), but not by the non-osteoclastogenetic anti-MDA/MAA clones or control antibodies. The glycolysis inhibitor 2-deoxyglucose completely abolished the osteoclastogenetic effect of the anti-MDA/MAA clones at drug concentrations that did not influenced baseline OC development. Fab2 fragments of the osteocalstogenetic anti-MDA/MAA clones had no effect on OC development and metabolism. In accordance with this, Fc-gamma receptor I neutralizing antibodies completely abolished the osteocalstogenetic effect of the anti-MDA/MAA clones. The osteoclastogenetic effect of the anti-MDA/MAA antibodies was independent of IL-8 production. In contrast to anti MDA/MAA antibodies, ACPA-mediated osteoclastogenesis was independent of glycolysis and Fc-gamma receptors but dependent on IL-8.Conclusion:Our results describe a novel glycolysis-dependent mechanism by which anti-MDA/MAA antibodies promote osteoclast development that is different from the one previously described for ACPA.References:[1] C. Grönwall et al. Journal of Autoimmunity 84 (2017) 29-45.[2] C. Wang et al. Arthritis and Rheumatism 62 (2010) 2064-2072Disclosure of Interests:Koji Sakuraba: None declared, Akilan Krishnamurthy: None declared, Alexandra Circiumaru: None declared, Meng Sun: None declared, Vijay Joshua: None declared, Marianne Engström: None declared, Xiaowei Zheng: None declared, Cheng Xu: None declared, Khaled Amara: None declared, Vivianne Malmström Grant/research support from: VM has had research grants from Janssen Pharmaceutica, Sergiu-Bogdan Catrina: None declared, Caroline Grönwall: None declared, Bence Réthi: None declared, Anca Catrina: None declared
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- Sakuraba, K, et al.
(författare)
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METABOLIC CHANGES INDUCED BY ANTI-MALONDIALDEHYDE/MALINDIALDEHYDE- ACETALDEHYDE ANTIBODIES PROMOTE OSTEOCLAST DEVELOPMENT
- 2021
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 429-429
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Malondialdehyde (MDA) is a highly reactive compound generated during lipid-peroxidation in conditions associated with oxidative stress. MDA can irreversibly modify proteins (e.g. lysine, arginine and histidine residues). In addition, acetaldehyde can further react with MDA adducts to form malondialdehyde-acetaldehyde (MAA) modification. Such protein modifications can lead to immunogenic neo-epitopes that are recognized by autoantibodies. In fact, anti-MDA/MAA IgG antibodies are significantly increased in the serum of patients with autoimmune diseases, such as rheumatoid arthritis (RA) (1). Interestingly, anti-MDA/MAA antibodies have been shown to promote osteoclast (OC) differentiation in vitro suggesting a potential role for these autoantibodies in bone damage associated with RA (1).Objectives:Little is known about the molecular mechanisms activated by autoantibodies in RA. Here, we elucidate the pathways specifically triggered by anti-MDA/MAA autoantibodies in developing osteoclasts.Methods:Recombinant human monoclonal anti-MDA/MAA antibodies, which were previously cloned from single synovial B cells of RA patients, were added to different OC assays. OCs were generated from monocyte-derived macrophages in the presence of the cytokines RANK-L and M-CSF. OC development was monitored by light microscopy following tartrate-resistant acid phosphatase staining and by erosion assays using calcium phosphate-coated plates. Bone morphometrics were studied in anti-MDA/MAA-injected mice using X-ray microscopy. Cellular metabolism was analyzed by mass spectrometry, Seahorse XF Analyzer and a colorimetric L-Lactate assay.Results:Anti-MDA/MAA antibodies induced a robust OC differentiation in vitro and bone loss in vivo. The anti-MDA/MAA antibodies acted on developing OCs by increasing glycolysis via an Fcγ receptor I-mediated pathway and the upregulation of the transcription factors HIF-1α, Myc and CHREBP. Such regulation of cellular metabolism was exclusively observed in the presence of the osteoclastogenic anti-MDA/MAA clones, whereas other RA-associated autoantibodies (anti-MDA/MAA or anti-citrullinated protein antibodies) had no effect on metabolism. The anti-MDA/MAA treatment induced a shift in the tricarboxylic acid (TCA) cycle activity in developing OCs, leading to the accumulation of citrate and aconitate.Conclusion:We described a novel type of autoantibody-induced pathway in RA, which might contribute to increased OC activation and a consequent bone loss. Anti-MDA/MAA antibodies promoted osteoclast development by increasing glycolysis and by modulating the TCA cycle through a signaling pathway that included Fcγ receptor I and a network of transcription factors acting on glycolysis. A TCA cycle bias towards citrate production suggests that the anti-MDA/MAA antibodies might stimulate OCs via increasing lipid biosynthesis in the cells.References:[1]Grönwall C. et al. J. Autoimmunity 84 (2017): 29-45.Acknowledgements:This Project has received funding from FOREUM, Foundation for Research in Rheumatology, from the European Research Council (ERC) grant agreement CoG 2017 - 7722209_PREVENT RA, the EU/EFPIA Innovative Medicine Initiative grant agreement 777357_RTCure, the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse and Knut and Alice Wallenberg Foundation.Disclosure of Interests:Koji Sakuraba: None declared, Akilan Krishnamurthy: None declared, Alexandra Circiumaru: None declared, Vijay Joshua: None declared, Heidi Wähämaa: None declared, Marianne Engström: None declared, Meng Sun: None declared, Xiaowei Zheng: None declared, Cheng Xu: None declared, Khaled Amara: None declared, Vivianne Malmström Grant/research support from: collaboration with Pfizer, unrelated to the abstract, Sergiu-Bogdan Catrina: None declared, Caroline Grönwall: None declared, Bence Réthi: None declared, Anca Catrina Grant/research support from: collaboration with BMS and Pfizer, unrelated to the present abstract
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