mTOR inhibition rescues osteopenia in mice with systemic sclerosis.
mTOR inhibition rescues osteopenia in mice with systemic sclerosis.
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DOI：
10.1084/jem.20140643
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发表时间：
2015-01-12
期刊：
影响因子：
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通讯作者：
Shi S
中科院分区：
文献类型：
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作者：
Chen C;Akiyama K;Wang D;Xu X;Li B;Moshaverinia A;Brombacher F;Sun L;Shi S
Chen等人表明，用雷帕霉素（一种已知抑制mTOR信号传导的药物）治疗可挽救患有系统性硬化症的小鼠的低骨密度。原纤维蛋白-1（FBN 1）缺乏诱导的系统性硬化症归因于白细胞介素-4（IL-4）和TGF-β的升高，但FBN 1缺乏相关的骨质减少的潜在机制尚未完全了解。我们发现，来自FBN 1缺陷（Fbn 1 +/−）小鼠的骨髓间充质干细胞（BMMSCs）表现出成骨分化减少和成脂分化增加。从机制上讲，这种谱系改变是由IL 4/IL 4 R α介导的mTOR信号转导激活调节的，通过P70核糖体S6蛋白激酶（P70 S6 K）分别下调RUNX 2和上调PPARγ2。此外，我们发现TGF-β/SMAD 3/SP1信号转导的激活导致SP1与IL 4 R α启动子的结合增强，从而协同激活Fbn 1 +/− BMMSC中的mTOR通路。通过成骨细胞特异性敲除或雷帕霉素治疗阻断mTOR信号传导通过改善BMMSC的成骨分化挽救Fbn 1 +/−小鼠的骨量减少表型总的来说，这项研究确定了FBN 1/TGF-β/IL 4 R α/mTOR级联在BMMSC谱系选择中的先前未被认识的作用，并提供了实验证据，表明雷帕霉素治疗可能为Fbn 1 +/−小鼠的骨质减少提供合成代谢治疗。
Chen et al. show that treatment with rapamycin, a drug known to inhibit mTOR signaling, rescues low bone density in mice with systemic sclerosis. 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.