戴尅戎院士Cell Death Dis文章：骨质疏松新机制

近日，国际生物医学学术期刊Cell Death and Disease在线发表了中科院上海生命科学研究院健康科学研究所戴尅戎研究组题研究论文，从骨髓间充质干细胞（Bone Marrow Stromal Cells, BMSCs）定向分化命运选择及调控的角度，揭示激素诱导型骨质疏松的发病新机制及治疗靶点。

　　

　近日，国际生物医学学术期刊Cell Death and Disease在线发表了中科院上海生命科学研究院健康科学研究所戴尅戎研究组题为Dexamethasone shifts bone marrow stromal cells from osteoblasts to adipocytes by C/EBPalpha promoter methylation的研究论文，从骨髓间充质干细胞（Bone Marrow Stromal Cells, BMSCs）定向分化命运选择及调控的角度，揭示激素诱导型骨质疏松的发病新机制及治疗靶点。

　　博士研究生李姣等在戴尅戎院士及张晓玲研究员的指导下发现，临床上长期使用糖皮质激素的病人在发生骨质疏松的同时，骨髓中出现大量的脂肪组织。在本研究中，他们从BMSCs定向分化调控的角度出发，来找寻激素诱导型骨质疏松的发病机制及其中的治疗靶点。研究发现，经过糖皮质激素地塞米松处理后的BMSC更容易向脂肪细胞分化，而向成骨细胞分化的能力降低。  

    进一步实验证实，地塞米松可以抑制成骨细胞分化中关键的Wnt/beta-catenin通路，导致启动脂肪细胞分化的转录因子C/EBPalpha启动子甲基化受到抑制而高度表达，在后者的作用下，BMSCs在成骨分化条件下也转而分化为脂肪细胞。同时，研究中通过抑制C/EBPalpha或者重新激活Wnt通路都成功挽救了地塞米松导致的成骨/成脂肪分化失衡，为临床上治疗激素类骨质疏松提供了新思路及药物靶点。

    该研究不仅从分子水平上深入探讨了BMSCs分化命运选择及调控的新机制，还通过动物模型将实验理论与临床疾病相结合，建立了基础研究向临床转化的平台。 糖皮质激素类药物如地塞米松一直是临床上使用最多的免疫抑制剂，广泛用于治疗自身免疫性疾病、移植后免疫排斥以及多种炎症。然而，长期使用这类药物会导致骨质疏松，甚至会发展为股骨头坏死，目前临床上尚无有效的治疗方法。

　　此项课题研究获得国家科技部、国家自然科学基金委、中国科学院战略性先导科技专项、上海市科委及上海市教委的经费资助。

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.