Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, 4301W. Markham, Little Rock, AR, 72205, USA.
Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, CA, 92093-0682, USA.
Nat Commun. 2018 Jun 6;9(1):2193. doi: 10.1038/s41467-018-04047-5.
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.
动脉粥样硬化和骨质疏松症在流行病学上有关联，氧化特异性表位（OSEs），如氧化磷脂（PC-OxPL）中的磷酸胆碱（PC）和丙二醛（MDA），在这两种疾病中都具有致病性。OSEs 的促动脉粥样硬化作用被先天免疫抗体所拮抗。在这里，我们发现表达可中和 PC-OxPL 的 IgM E06 的单链可变区片段（E06-scFv）的高脂肪饮食（HFD）诱导的小鼠骨丢失得到了减弱，这是通过增加成骨细胞数量和刺激骨形成来实现的。类似地，表达中和 MDA 的 IK17-scFv 的小鼠的 HFD 诱导的骨丢失也得到了减弱。值得注意的是，E06-scFv 还增加了正常饮食喂养的小鼠的骨量。此外，老年小鼠的抗 PC IgM 水平降低。我们得出结论，OSEs，无论是慢性产生还是由 HFD 增加，都会抑制骨形成，而对 OSEs 的防御减弱可能导致与年龄相关的骨丢失。因此，抗-OSEs 可能代表了一种针对骨质疏松症和动脉粥样硬化的新的治疗方法。
