Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice,Aging Cell

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Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice
Aging Cell ( IF 8.0 ) Pub Date : 2021-07-19 , DOI: 10.1111/acel.13442
Michela Palmieri ₁ , Maria Almeida ₁ , Intawat Nookaew ₂ , Horacio Gomez-Acevedo ₂ , Teenamol E Joseph ₁ , Xuchu Que ₃ , Sotirios Tsimikas ₄ , Xiaoli Sun ₃ , Stavros C Manolagas ₁ , Joseph L Witztum ₃ , Elena Ambrogini ₁

Affiliation

Oxidized phospholipids (OxPLs) are pro-inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single-chain variable fragment (scFv) of the antigen-binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age-related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age-related bone loss. We show here that transgenic expression of E06-scFv attenuated the age-associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06-scFv attenuated the age-associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA-seq analysis showed that E06-scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age-related bone loss, E06-scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age-associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non-alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06-scFv in mice.

中文翻译：

氧化磷脂的中和可减轻小鼠与年龄相关的骨质流失

氧化磷脂 (OxPLs) 是在生理条件下影响骨重塑的促炎分子。E06 抗原结合结构域单链可变片段 (scFv) 的转基因表达是一种 IgM 天然抗体，可识别 OxPLs 的磷酸胆碱 (PC) 部分，通过增加骨量增加成年雄性和雌性小鼠的骨小梁和皮质骨形成。OxPLs 随着年龄的增长而增加，而天然抗体减少。年龄相关性骨质流失与氧化应激和脂质过氧化增加有关，其特征是成骨细胞数量和骨形成减少，这增加了 OxPLs 增加以及天然抗体下降导致年龄相关性骨质流失的可能性。我们在这里展示了 E06-scFv 的转基因表达减弱了与年龄相关的脊髓损失，雌性和雄性小鼠的股骨密度和总骨密度分别为 22 个月和 24 个月。E06-scFv 减弱了与年龄相关的骨小梁下降，但不减弱皮质骨，这种作用与成骨细胞的增加和破骨细胞的减少有关。此外，RNA-seq 分析显示 E06-scFv 增加了老年小鼠椎骨中 Wnt10b 的表达，表明阻断 OxPLs 增加了 Wnt 信号传导。与年龄相关的骨质流失不同，E06-scFv 并未减轻成年小鼠因雌激素缺乏或卸载引起的骨质流失。这些结果表明，OxPL 会导致与年龄相关的骨质流失。因此，中和 OxPLs 是老年骨质疏松症以及动脉粥样硬化和非酒精性脂肪性肝炎 (NASH) 的有希望的治疗靶点，

更新日期：2021-08-19

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