目的：血管钙化（VC）和骨质疏松曾被认为是两种不同的疾病。然而，当前的理解表明它们具有共同的发病机制。治疗VC和骨质疏松的药物有限。我们以前证明了发酵乳肽（KPs）缓解了高脂肪饮食（HFD）诱导的apoE敲除小鼠动脉粥样硬化。本研究进一步研究了KPs对apoE敲除小鼠高胆固醇动脉粥样硬化饮食（AD）引起的VC和骨质疏松的预防作用。主要方法：7周龄的apoE敲除和野生型C57BL/6小鼠被随机分成五组（n=6）。经AD饲喂13周后，评估了KP处理的apoE敲除小鼠VC和骨质疏松的发展情况，并将其与饲喂标准饲料（CD）的C57BL/6和apoE敲除小鼠进行比较。主要发现：结果表明，KP处理的apoE敲除小鼠血清总胆固醇、氧化低密度脂蛋白（ox-LDL）、丙二醛（MDA）水平和血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和肌酸激酶（CK）活性降低，表明KPs预防了apoE敲除小鼠的高脂血症并可能对肝脏和肌肉产生损害。KPs减少了AD饲喂apoE敲除小鼠主动脉组织中肿瘤坏死因子-α（TNF-α）和局部TNF-α、IL-1β和巨噬细胞特异性CD68标志物的表达，表明KPs抑制了AD饲喂apoE敲除小鼠的炎症反应。KPs减少了AD饲喂apoE敲除小鼠主动脉根部的脂质、胶原和钙矿质沉积，表明KPs抑制了动脉粥样硬化斑块的钙化进展。KPs在AD饲喂apoE敲除小鼠中表现出骨保护作用，这表现为骨吸收标志物CTX-1水平较低，骨形成标志物P1NP水平较高。KPs改善了股骨的皮质骨密度和骨体积，并减少了梭形骨的骨量减少。意义：本研究表明，KPs通过减少AD饲喂apoE敲除小鼠的氧化应激和炎症反应减轻了VC和骨质疏松。我们的研究为将KPs应用于预防高脂血症引起的血管和骨骼退化的治疗药物中做出了贡献。版权所有©2023昌，成，范，陈，兰，陈，颜和陈。

Aims: Vascular calcification (VC) and osteoporosis were previously considered two distinct diseases. However, current understanding indicates that they share common pathogenetic mechanisms. The available medicines for treating VC and osteoporosis are limited. We previously demonstrated that kefir peptides (KPs) alleviated atherosclerosis in high-fat diet (HFD)-induced apolipoprotein E knockout (ApoE -/- ) mice. The present study further addressed the preventive effects of KPs on VC and osteoporosis in ApoE -/- mice fed a high-cholesterol atherogenic diet (AD). Main methods: Seven-week-old ApoE -/- and wild-type C57BL/6 mice were randomly divided into five groups (n = 6). The development of VC and osteoporosis was evaluated after AD feeding for 13 weeks in KP-treated ApoE -/- mice and compared to C57BL/6 and ApoE -/- mice fed a standard chow diet (CD). Key findings: The results indicated that KP-treated ApoE -/- mice exhibited lower serum total cholesterol, oxidized low-density lipoprotein (ox-LDL), malondialdehyde (MDA) levels, and serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine kinase (CK) activities, which suggested that KPs prevented hyperlipidemia and possible damages to the liver and muscle in ApoE -/- mice. KPs reduced serum tumor necrosis factor-α (TNF-α) and the local expression of TNF-α, IL-1β, and macrophage-specific CD68 markers in aortic tissues, which suggested that KPs inhibited inflammatory responses in AD-fed ApoE -/- mice. KPs reduced the deposition of lipid, collagen, and calcium minerals in the aortic roots of AD-fed ApoE -/- mice, which suggested that KPs inhibited the calcific progression of atherosclerotic plaques. KPs exerted osteoprotective effects in AD-fed ApoE -/- mice, which was evidenced by lower levels of the bone resorption marker CTX-1 and higher levels of the bone formation marker P1NP. KPs improved cortical bone mineral density and bone volume and reduced trabecular bone loss in femurs. Significance: The present data suggested that KPs attenuated VC and osteoporosis by reducing oxidative stress and inflammatory responses in AD-fed ApoE -/- mice. Our findings contribute to the application of KPs as preventive medicines for the treatment of hyperlipidemia-induced vascular and bone degeneration.Copyright © 2023 Chang, Cheng, Fan, Chen, Lan, Chen, Yen and Chen.