Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine.
Swedish mutant APP suppresses osteoblast differentiation and causes osteoporotic deficit, which are ameliorated by N-acetyl-L-cysteine.
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DOI：
10.1002/jbmr.1954
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Xia WF;Jung JU;Shun C;Xiong S;Xiong L;Shi XM;Mei L;Xiong WC
阿尔茨海默病（AD）患者经常观察到骨密度降低和髋部骨折。然而，它们之间联系的机制仍然知之甚少。淀粉样前体蛋白（APP）是一种跨膜蛋白，在骨髓基质细胞（BMSCs）、成骨细胞（OBs）、巨噬细胞（BMMs）和破骨细胞（OCs）中普遍表达。在早发性AD患者中发现的APP基因突变被认为是导致AD的原因。但APP在骨重塑中的作用知之甚少。在这里，我们提出了瑞典突变体APP （APPswe）在培养和小鼠中抑制OB分化和功能的证据。APP在骨髓间充质干细胞中的表达随着年龄的增长而增加。APPswe在年轻成年Tg2576转基因小鼠（在朊病毒启动子控制下）中的普遍表达重现了骨骼“衰老样”缺陷，包括OB发生和骨形成减少，脂肪生成和骨髓脂肪增加，OC发生和骨吸收增强。值得注意的是，在TgAPPswe-Ocn小鼠成熟OB系细胞中选择性表达APPswe（在骨钙素[Ocn]启动子驱动的Cre控制下）也会减少OB的发生，增加OC的形成，导致小梁骨丢失。因此，这些结果表明APPswe在抑制OB形成和功能方面具有细胞自主作用，但在OC发生方面具有非自主作用。值得注意的是，在年轻成年Tg2576小鼠中检测到脂肪生成增加和骨髓脂肪升高，而在TgAPPswe-Ocn小鼠中未检测到，这表明骨髓间充质干细胞和/或骨髓多细胞类型中的APPswe促进了骨髓脂肪生成。有趣的是，年轻成年Tg2576小鼠的骨骼衰老样缺陷可以通过抗氧化剂n -乙酰-l -半胱氨酸（NAC）治疗来预防，这表明活性氧（ROS）可能是appswee诱导的骨质疏松症缺陷的基础。综上所述，这些结果证明了APPswe在抑制OB分化和骨形成方面的作用，暗示APPswe是ad相关骨质疏松缺陷的有害因素，并揭示了NAC在治疗骨质疏松缺陷方面的潜在临床价值。
Reduced bone mineral density and hip fracture are frequently observed in patients with Alzheimer’s disease (AD). However, mechanisms underlying their association remain poorly understood. Amyloid precursor protein (APP) is a transmembrane protein that is ubiquitously expressed in bone marrow stromal cells (BMSCs), osteoblasts (OBs), macrophages (BMMs), and osteoclasts (OCs). Mutations in the APP gene identified in early-onset AD patients are believed to cause AD. But little is known about APP’s role in bone remodeling. Here, we present evidence for Swedish mutant APP (APPswe) in suppression of OB differentiation and function in culture and in mouse. APP expression in BMSCs increases during aging. Ubiquitous expression of APPswe in young adult Tg2576 transgenic mice (under the control of a prion promoter) recaptured skeletal “aging-like” deficits, including decreased OB genesis and bone formation, increased adipogenesis and bone marrow fat, and enhanced OC genesis and bone resorption. Remarkably, selective expression of APPswe in mature OB-lineage cells in TgAPPswe-Ocn mice (under the control of osteocalcin [Ocn] promoter-driven Cre) also decreased OB genesis and increased OC formation, resulting in a trabecular bone loss. These results thus suggest a cell-autonomous role for APPswe in suppressing OB formation and function, but a nonautonomous effect on OC genesis. Notably, increased adipogenesis and elevated bone marrow fat were detected in young adult Tg2576 mice, but not in TgAPPswe-Ocn mice, implying that APPswe in BMSCs and/or multicell types in bone marrow promotes bone marrow adipogenesis. Intriguingly, the skeletal aging-like deficits in young adult Tg2576 mice were prevented by treatment with N-acetyl-L-cysteine (NAC),an antioxidant, suggesting that reactive oxygen species (ROS) may underlie APPswe-induced osteoporotic deficits. Taken together, these results demonstrate a role for APPswe in suppressing OB differentiation and bone formation, implicate APPswe as a detrimental factor for AD-associated osteoporotic deficit, and reveal a potential clinical value of NAC in the treatment of osteoporotic deficits.
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影响因子：
29
作者：
Ambrogini E;Almeida M;Martin-Millan M;Paik JH;Depinho RA;Han L;Goellner J;Weinstein RS;Jilka RL;O'Brien CA;Manolagas SC
通讯作者：
Manolagas SC
影响因子：
6.2
作者：
Cui, Shun;Xiong, Fei;Hong, Yan;Jung, Ji-Ung;Li, Xing-Sheng;Liu, Jian-Zhong;Yan, Riqiang;Mei, Lin;Feng, Xu;Xiong, Wen-Cheng
通讯作者：
Xiong, Wen-Cheng
影响因子：
4.2
作者：
Huang, Quanzhen;Aluise, Christopher D.;Butterfield, D. Allan
通讯作者：
Butterfield, D. Allan
影响因子：
3.4
作者：
Koistinen, Hannu;Prinjha, Rab;Dingwall, Colin
通讯作者：
Dingwall, Colin
影响因子：
6.1
作者：
Asante, EA;Gowland, I;Collinge, J
通讯作者：
Collinge, J