Oxidation-specific epitopes restrain bone formation

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

doi:10.1038/s41467-018-04047-5

Abstract

Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both. The proatherogenic effects of OSEs are opposed by innate immune antibodies. Here we show that high-fat diet (HFD)-induced bone loss is attenuated in mice expressing a single chain variable region fragment of the IgM E06 (E06-scFv) that neutralizes PC-OxPL, by increasing osteoblast number and stimulating bone formation. Similarly, HFD-induced bone loss is attenuated in mice expressing IK17-scFv, which neutralizes MDA. Notably, E06-scFv also increases bone mass in mice fed a normal diet. Moreover, the levels of anti-PC IgM decrease in aged mice. We conclude that OSEs, whether produced chronically or increased by HFD, restrain bone formation, and that diminished defense against OSEs may contribute to age-related bone loss. Anti-OSEs, therefore, may represent a novel therapeutic approach against osteoporosis and atherosclerosis simultaneously.

Highlights

Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both
We found that the E06-scFv transgene increases cancellous bone mass and attenuates the loss of cortical bone mass caused by high fat diet (HFD) in the LDLreceptor knockout (LDLR-KO) model of atherosclerosis
Having observed an anabolic effect of two different anti-OSE antibodies in the context of atherosclerosis induced by high-fat diet (HFD), we examined whether the overexpression of one of them (E06-scFv) had an effect on bone of mice maintained on a normal diet

Summary

Introduction

Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both. We show that high-fat diet (HFD)-induced bone loss is attenuated in mice expressing a single chain variable region fragment of the IgM E06 (E06-scFv) that neutralizes PC-OxPL, by increasing osteoblast number and stimulating bone formation. Lipid peroxidation generates highly reactive degradation products such as malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and oxidized phospholipids (OxPL), such as oxidized phosphatidylcholine These moieties react with amino groups on proteins and other lipids to form adducts that are collectively known as oxidation-specific epitopes (OSEs)[11]. NAbs are predominantly of the IgM class and comprise about 80% of the total serum IgM in uninfected mice[19] Their antigen binding sites are generated by rearrangement of germline-encoded variable region genes in the complete absence of foreign antigen exposure. Similar to E06, both the murine NAb E014 and the human IK17, recognize MDA and prevent the proinflammatory effect of MDA on macrophages[11,21]

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Conclusion