近日，國際生物醫(yī)學(xué)學(xué)術(shù)期刊Cell Death and Disease在線發(fā)表了中科院上海生命科學(xué)研究院健康科學(xué)研究所戴尅戎研究組題為Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation的研究論文，從骨髓間充質(zhì)干細(xì)胞（Bone Marrow Stromal Cells, BMSCs）定向分化命運(yùn)選擇及調(diào)控的角度，揭示激素誘導(dǎo)型骨質(zhì)疏松的發(fā)病新機(jī)制及治療靶點(diǎn)。

　　博士研究生李姣等在戴尅戎院士及張曉玲研究員的指導(dǎo)下發(fā)現(xiàn)，臨床上長期使用糖皮質(zhì)激素的病人在發(fā)生骨質(zhì)疏松的同時，骨髓中出現(xiàn)大量的脂肪組織。在本研究中，他們從BMSCs定向分化調(diào)控的角度出發(fā)，來找尋激素誘導(dǎo)型骨質(zhì)疏松的發(fā)病機(jī)制及其中的治療靶點(diǎn)。研究發(fā)現(xiàn)，經(jīng)過糖皮質(zhì)激素地塞米松處理后的BMSC更容易向脂肪細(xì)胞分化，而向成骨細(xì)胞分化的能力降低。  

    進(jìn)一步實(shí)驗(yàn)證實(shí)，地塞米松可以抑制成骨細(xì)胞分化中關(guān)鍵的Wnt/beta-catenin通路，導(dǎo)致啟動脂肪細(xì)胞分化的轉(zhuǎn)錄因子C/EBPalpha啟動子甲基化受到抑制而高度表達(dá)，在后者的作用下，BMSCs在成骨分化條件下也轉(zhuǎn)而分化為脂肪細(xì)胞。同時，研究中通過抑制C/EBPalpha或者重新激活Wnt通路都成功挽救了地塞米松導(dǎo)致的成骨/成脂肪分化失衡，為臨床上治療激素類骨質(zhì)疏松提供了新思路及藥物靶點(diǎn)。

    該研究不僅從分子水平上深入探討了BMSCs分化命運(yùn)選擇及調(diào)控的新機(jī)制，還通過動物模型將實(shí)驗(yàn)理論與臨床疾病相結(jié)合，建立了基礎(chǔ)研究向臨床轉(zhuǎn)化的平臺。 糖皮質(zhì)激素類藥物如地塞米松一直是臨床上使用最多的免疫抑制劑，廣泛用于治療自身免疫性疾病、移植后免疫排斥以及多種炎癥。然而，長期使用這類藥物會導(dǎo)致骨質(zhì)疏松，甚至?xí)�發(fā)展為股骨頭壞死，目前臨床上尚無有效的治療方法。

　　此項(xiàng)課題研究獲得國家科技部、國家自然科學(xué)基金委、中國科學(xué)院戰(zhàn)略性先導(dǎo)科技專項(xiàng)、上海市科委及上海市教委的經(jīng)費(fèi)資助。

原文摘要：
Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation

Dexamethasone (Dex)-induced osteoporosis has been described as the most severe side effect in long-term glucocorticoid therapy. The decreased bone mass and the increased marrow fat suggest that Dex possibly shifts the differentiation of bone marrow stromal cells (BMSCs) to favor adipocyte over osteoblast, but the underlying mechanisms are still unknown. In this paper, we established a Dex-induced osteoporotic mouse model, and found that BMSCs from Dex-treated mice are more likely to differentiate into adipocyte than those from control mice, even under the induction of bone morphogenetic protein-2 (BMP2). We also discovered both in vitro and in vivo that the expression level of adipocyte regulator CCAAT/enhancer-binding protein alpha (C/EBPalpha) is significantly upregulated in Dex-induced osteoporotic BMSCs during osteoblastogenesis by a mechanism that involves inhibited DNA hypermethylation of its promoter. Knockdown of C/EBPalpha in Dex-induced osteoporotic cells rescues their differentiation potential, suggesting that Dex shifts BMSC differentiation by inhibiting C/EBPalpha promoter methylation and upregulating its expression level. We further found that the Wnt/beta-catenin pathway is involved in Dex-induced osteoporosis and C/EBPalpha promoter methylation, and its activation by LiCl rescues the effect of Dex on C/EBPalpha promoter methylation and osteoblast/adipocyte balance. This study revealed the C/EBPalpha promoter methylation mechanism and evaluated the function of Wnt/beta-catenin pathway in Dex-induced osteoporosis, providing a useful therapeutic target for this type of osteoporosis.