Novel Hedgehog Agonists Promote Osteoblast Differentiation in Mesenchymal Stem Cells
Novel Hedgehog Agonists Promote Osteoblast Differentiation in Mesenchymal Stem Cells
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DOI：
10.1002/jcp.24823
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发表时间：
2015-04
影响因子：
5.6
通讯作者：
Takashi Nakamura;M. Naruse;Y. Chiba;T. Komori;K. Sasaki;M. Iwamoto;S. Fukumoto
中科院分区：
文献类型：
--
作者：
Takashi Nakamura;M. Naruse;Y. Chiba;T. Komori;K. Sasaki;M. Iwamoto;S. Fukumoto
Hhedgehog(HH)家族成员参与多种细胞过程，包括增殖、迁移、分化和决定细胞命运。最近，在高通量的小分子化合物筛选中发现了新的HH激动剂HH-Ag1.3和1.7，这些小分子化合物可以激活HH信号的靶标Gli1的表达。本研究表明，HH-Ag1.3和1.7在间充质干细胞株C3H10T1/2中强烈激活内源性Gli1的表达，促进成骨细胞分化。两种化合物均以剂量依赖的方式刺激C3H10T1/2细胞的碱性磷酸酶活性，并诱导成骨细胞标志基因的表达，表明其已获得成骨细胞特性。其中，HH-Ag1.7可诱导Runt相关转录因子(RUNX)2下游靶基因Osterix/SP7的表达，挽救Runx2基因缺陷小鼠间充质细胞系RD-127的成骨细胞分化缺陷。HH-AGS还激活了典型的Wnt信号，并与低剂量的BMP-2协同增强成骨潜能。因此，HH-Ag 1.7可用于骨质疏松症患者和老年人等骨形成异常个体的骨愈合，并有助于开发治疗骨骨折和骨缺损的新疗法。J.细胞。物理。2015年，230：922-929。©2014 Wiley期刊，Inc.
Hedgehog (Hh) family members are involved in multiple cellular processes including proliferation, migration, differentiation, and cell fate determination. Recently, the novel Hh agonists Hh‐Ag 1.3 and 1.7 were identified in a high‐throughput screening of small molecule compounds that activate the expression of Gli1, a target of Hh signaling. This study demonstrates that Hh‐Ag 1.3 and 1.7 strongly activate the expression of endogenous Gli1 and promote osteoblast differentiation in the mesenchymal stem cell line C3H10T1/2. Both compounds stimulated alkaline phosphatase activity in a dose‐dependent manner, and induced osteoblast marker gene expression in C3H10T1/2 cells, which indicated that they had acquired an osteoblast identity. Of the markers, the expression of osterix/Sp7, a downstream target of runt‐related transcription factor (Runx)2, was induced by Hh‐Ag 1.7, which also rescued the osteoblast differentiation defect of RD‐127, a mesenchymal cell line from Runx2‐deficient mice. Hh‐Ags also activated canonical Wnt signaling and synergized with low doses of BMP‐2 to enhance osteoblastic potential. Thus, Hh‐Ag 1.7 could be useful for bone healing in individuals with abnormalities in osteogenesis, such as osteoporosis patients and the elderly, and can contribute to the development of novel therapeutics for the treatment of bone fractures and defects. J. Cell. Physiol. 230: 922–929, 2015. © 2014 Wiley Periodicals, Inc.