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mTOR抑制可挽救系统性硬化症小鼠的骨质减少。

mTOR inhibition rescues osteopenia in mice with systemic sclerosis.

作者信息

Chen Chider, Akiyama Kentaro, Wang Dandan, Xu Xingtian, Li Bei, Moshaverinia Alireza, Brombacher Frank, Sun Lingyun, Shi Songtao

机构信息

Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033 Department of Oral Rehabilitation and Regenerative Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science, Kita-ku, Okayama 700-8525, Japan.

出版信息

J Exp Med. 2015 Jan 12;212(1):73-91. doi: 10.1084/jem.20140643. Epub 2014 Dec 22.

DOI:10.1084/jem.20140643
PMID:25534817
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4291526/
Abstract

Fibrillin-1 (FBN1) deficiency-induced systemic sclerosis is attributed to elevation of interleukin-4 (IL4) and TGF-β, but the mechanism underlying FBN1 deficiency-associated osteopenia is not fully understood. We show that bone marrow mesenchymal stem cells (BMMSCs) from FBN1-deficient (Fbn1(+/-)) mice exhibit decreased osteogenic differentiation and increased adipogenic differentiation. Mechanistically, this lineage alteration is regulated by IL4/IL4Rα-mediated activation of mTOR signaling to down-regulate RUNX2 and up-regulate PPARγ2, respectively, via P70 ribosomal S6 protein kinase (P70S6K). Additionally, we reveal that activation of TGF-β/SMAD3/SP1 signaling results in enhancement of SP1 binding to the IL4Rα promoter to synergistically activate mTOR pathway in Fbn1(+/-) BMMSCs. Blockage of mTOR signaling by osteoblastic-specific knockout or rapamycin treatment rescues osteopenia phenotype in Fbn1(+/-) mice by improving osteogenic differentiation of BMMSCs. Collectively, this study identifies a previously unrecognized role of the FBN1/TGF-β/IL4Rα/mTOR cascade in BMMSC lineage selection and provides experimental evidence that rapamycin treatment may provide an anabolic therapy for osteopenia in Fbn1(+/-) mice.

摘要

原纤蛋白-1（FBN1）缺乏诱导的系统性硬化症归因于白细胞介素-4（IL4）和转化生长因子-β（TGF-β）的升高，但FBN1缺乏相关骨质减少的潜在机制尚未完全阐明。我们发现，来自FBN1缺陷（Fbn1(+/-)）小鼠的骨髓间充质干细胞（BMMSC）表现出成骨分化减少和脂肪生成分化增加。从机制上讲，这种谱系改变分别通过P70核糖体S6蛋白激酶（P70S6K）由IL4/IL4Rα介导的mTOR信号激活来调节，从而分别下调RUNX2和上调PPARγ2。此外，我们发现TGF-β/SMAD3/SP1信号的激活导致SP1与IL4Rα启动子的结合增强，从而协同激活Fbn1(+/-) BMMSC中的mTOR途径。通过成骨细胞特异性敲除或雷帕霉素处理阻断mTOR信号，可通过改善BMMSC的成骨分化来挽救Fbn1(+/-)小鼠的骨质减少表型。总的来说，这项研究确定了FBN1/TGF-β/IL4Rα/mTOR级联在BMMSC谱系选择中以前未被认识的作用，并提供了实验证据表明雷帕霉素治疗可能为Fbn1(+/-)小鼠的骨质减少提供一种合成代谢疗法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/fdc204837f48/JEM_20140643_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/3ecc7fba6da8/JEM_20140643_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/4ec441e04c3f/JEM_20140643_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/6e4050909361/JEM_20140643_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/eec6e76fe63e/JEM_20140643_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/902f63c755bd/JEM_20140643_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/72e012e7b1c6/JEM_20140643_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/22df1ff67772/JEM_20140643_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/9bf5e6ba7912/JEM_20140643R_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/413e4fa1d9d9/JEM_20140643R_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/fdc204837f48/JEM_20140643_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/3ecc7fba6da8/JEM_20140643_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/4ec441e04c3f/JEM_20140643_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/6e4050909361/JEM_20140643_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/eec6e76fe63e/JEM_20140643_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/902f63c755bd/JEM_20140643_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/72e012e7b1c6/JEM_20140643_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/22df1ff67772/JEM_20140643_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/9bf5e6ba7912/JEM_20140643R_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/413e4fa1d9d9/JEM_20140643R_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3005/4291526/fdc204837f48/JEM_20140643_Fig10.jpg

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