Oxidation-specific epitopes restrain bone formation

Ambrogini, Elena; Que, Xuchu; Wang, Shuling; Yamaguchi, Fuminori; Weinstein, Robert S.; Tsimikas, Sotirios; Manolagas, Stavros C.; Witztum, Joseph L.; Jilka, Robert L.

doi:10.1038/s41467-018-04047-5

Cited by 48 publications

(69 citation statements)

References 64 publications

(78 reference statements)

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“…The E06 transgenic mice can be used to study the mechanisms by which OxPL contributes to these disease processes in vivo , as well as other disease states in which OxPL may play a role. For example, we recently demonstrated with these mice that OxPL restrains bone formation in mice fed either a WD or chow diet 27 .…”

Section: Introductionmentioning

confidence: 99%

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Que

Hung

Yeang

et al. 2018

Nature

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420

336

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Section: Introductionmentioning

confidence: 99%

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Que

Hung

Yeang

et al. 2018

Nature

Self Cite

420

336

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“…Another evidence for pathogenic role of OxPC in vivo was obtained in an ischemia‐reperfusion model where overexpression of the E06 antibody fragment protected animals and reduced myocardial infarct size . One further in vivo study demonstrated the ability of the E06 antibody fragment to prevent bone loss induced by high fat diet in LDL receptor‐KO mice . In summary, these publications convincingly demonstrated that proinflammatory OxPC plays an important pathological role in vivo thus further pointing to the potential importance of circulating OxPLs as disease biomarkers.…”

Section: Structure and Biological Effects Of Oxplsmentioning

confidence: 83%

OxPLs‐Masking/Degradation Immune Assay: An “All‐Included” Analysis of Mechanisms Detoxifying Oxidized Phospholipids

Philippova¹,

Oskolkova

Bochkov

2019

Euro J Lipid Sci & Tech

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The manuscript discusses the use of circulating oxidized phospholipids (OxPLs) as potential disease biomarkers. Blood levels of OxPLs have been previously demonstrated to be strongly associated with cardiovascular disease. These data were obtained using an immune assay based on monoclonal antibody E06 which detects oxidized phosphatidylcholine. The impact of other classes of OxPLs on disease progression is not known. It is postulated that 1) other classes of OxPLs may contribute to cardiovascular disease and 2) both the absolute concentrations of OxPLs and the activity of detoxifying mechanisms are essential factors linking OxPLs with disease progression. Among such mechanisms is opsonization of OxPLs by endogenous antibodies and other plasma proteins. Furthermore, plasma contains enzymes degrading OxPLs. Experimental data from this study show that highly diluted blood plasma significantly reduces (“masks”) binding of E06, as well as another anti‐OxPL monoclonal antibody that recognizes oxidized phosphatidylethanolamine, to OxLDL. Potentially, sequestration or degradation of OxPLs by plasma proteins, antibodies or enzymes can ameliorate pathogenic effects of OxPLs, thus preventing disease onset. Based on these considerations, it is hypothesized that analysis of blood levels of “masking/degrading” proteins may provide important additional information complementary to the E06‐based assay and therefore improve its diagnostic value. Practical Applications: The manuscript discusses application of antibodies against OxPLs for their analysis as potential disease biomarkers. Plates are coated with OxLDL, blocked and incubated with either control buffer or plasma, which contains proteins and enzymes binding or degrading OxPLs present on OxLDL. Then the amount of remaining OxPLs is determined using monoclonal antibodies detecting OxPCs or OxPEs. The difference in signal intensities between the buffer‐ and plasma‐treated wells represents the activity of OxPLs‐masking/degradation.

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“…Therefore, endogenous formaldehyde may be elevated in people with ALDH2*1/*2 and ALDH2*2/*2. Recent studies have reported that aldehydes such as formaldehyde and acetaldehyde are complexed to form 1,4-dihydropyrdine-lysine adducts [3,6,28], which is an inflammatory, oxidation-specific epitope that can cause the inhibition of osteogenesis [29,30]. The increased formation of 1,4-dihydropyrdine-lysine adducts in the bone of individuals with the ALDH2*2 allele could cause worse osteoporosis than individuals with ALDH2*1/*1.…”

Section: Resultsmentioning

confidence: 99%

The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

et al. 2020

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Background: Exogenous formaldehyde is classified by the IARC as a Category 1 known human carcinogen. Meanwhile, a significant amount of endogenous formaldehyde is produced in the human body; as such, formaldehyde-derived DNA and protein adducts have been detected in animals and humans in the absence of major exogenous formaldehyde exposure. However, the toxicological effects of endogenous formaldehyde on individuals with normal DNA damage repair functions are not well understood. In this study, we attempted to generate C57BL/6 mice deficient in both Adh5 and Aldh2, which encode two major enzymes that metabolize endogenous formaldehyde, in order to understand the effects of endogenous formaldehyde on mice with normal DNA repair function. Results: Due to deficiencies in both ADH5 and ALDH2, few mice survived past post-natal day 21. In fact, the survival of pups within the first few days after birth was significantly decreased. Remarkably, two Aldh2 −/− /Adh5 −/− mice survived for 25 days after birth, and we measured their total body weight and organ weights. The body weight of Aldh2 −/− /Adh5 −/− mice decreased significantly by almost 37% compared to the Aldh2 −/− /Adh5 +/− and Aldh2 −/− /Adh5 +/+ mice of the same litter. In addition, the absolute weight of each organ was also significantly reduced. Conclusion: Mice deficient in both formaldehyde-metabolizing enzymes ADH5 and ALDH2 were found to develop partial synthetic lethality and mortality shortly after birth. This phenotype may be due to the accumulation of endogenous formaldehyde. No serious phenotype has been reported in people with dysfunctional, dominantnegative ALDH2*2 alleles, but it has been reported that they may be highly susceptible to osteoporosis and neurodegenerative diseases. It is important to further investigate these diseases in individuals with ALDH2*2 alleles, including an association with decreased metabolism, and thus accumulation, of formaldehyde.

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Oxidation-specific epitopes restrain bone formation

Cited by 48 publications

References 64 publications

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice

OxPLs‐Masking/Degradation Immune Assay: An “All‐Included” Analysis of Mechanisms Detoxifying Oxidized Phospholipids

The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

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