# Role of Natural Antibodies Against Oxidation Specific Epitopes in Bone Homeostasis

> **NIH VA I01** · CENTRAL ARKANSAS VETERANS HLTHCARE SYS · 2022 · —

## Abstract

Lipid peroxidation forms highly reactive molecules that generate adducts with amino groups of proteins and
lipids, known as oxidation specific epitopes (OSEs). OSEs are ubiquitous pro-inflammatory moieties that cause
extensive cell damage if not promptly eliminated. Natural antibodies of the innate immune system, recognize
OSEs and block their adverse effects. Scavenger receptors (SRs) expressed in macrophages and other cell
types recognize OSEs and dispose of oxidatively-modified endogenous molecules. Persistence and/or
excessive amounts of OSEs overwhelm these defense mechanisms, and the inflammatory response initiated
by scavenger receptor/toll-receptor activation causes tissue damage and the development of disease.
Phosphocholine-containing oxidized phospholipids (PC-OxPLs) form OSEs on oxidized low density
lipoproteins (OxLDLs) and on the surface of apoptotic cells. The IgM E06 is a natural antibody that recognizes
PC-OxPL. Transgenic mice expressing a single chain (scFv) form of the antigen-binding domain of E06 IgM
(E06-scFv) are protected against atherosclerosis and have increased lifespan. This effect results from the
prevention of OSE binding to macrophages and the subsequent activation of inflammatory pathways. In
humans, low levels of natural antibodies are associated with increased incidence of cardiovascular disease.
Epidemiologic evidence in humans as well as mechanistic studies in mice indicate that the OSE-rich OxLDL is
a pathogenic factor for osteoporosis as well. Remarkably, we found that the E06-scFv transgene prevents the
cortical bone loss caused by HFD by increasing endosteal osteoblast number and bone formation. In addition,
E06-scFv increases cancellous and cortical bone in male and female C57Bl/6J mice fed a normal diet by
increasing bone formation and osteoblast number. Mechanistic studies showed that E06 IgM prevents the
negative effects of OxLDL on proliferation, differentiation, and survival of cultured osteoblastic cells suggesting
that anti-OSE antibodies promote bone anabolism by preventing the negative effects of OSEs on osteoblasts.
Consistently, the production of anti-osteogenic cytokines by macrophages was not affected in E06-scFv
transgenic mice. Deletion of the scavenger receptor ScrB1, the most abundant scavenger receptor for PC-
OxPL in cells of the osteoblast lineage, prevents the adverse effects of OxLDL on apoptosis and differentiation.
Moreover, anti-PC IgM (which includes E06) decline with age in mice, in association with a decline in bone
mass. Therefore, we hypothesize that anti PC-OxPLs antibodies play a beneficial role in skeletal homeostasis
by protecting against deleterious effects of PC-OxPLs on bone formation, that are transmitted by ScrB1 on
osteoblasts. Increased production of OSEs due to accelerated apoptosis, oxidative stress, or chronic
inflammation, in concert with declining levels of anti PC-OxPLs antibodies with age, contributes to the
pathogenesis of osteoporosis in both mice and huma...

## Key facts

- **NIH application ID:** 10477223
- **Project number:** 5I01BX003901-04
- **Recipient organization:** CENTRAL ARKANSAS VETERANS HLTHCARE SYS
- **Principal Investigator:** Elena Ambrogini
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477223

## Citation

> US National Institutes of Health, RePORTER application 10477223, Role of Natural Antibodies Against Oxidation Specific Epitopes in Bone Homeostasis (5I01BX003901-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477223. Licensed CC0.

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