Schilling Tatjana, Küffner Robert, Klein-Hitpass Ludger, Zimmer Ralf, Jakob Franz, Schütze Norbert
University of Würzburg, Orthopedic Department, Orthopedic Center for Musculoskeletal Research, Würzburg, Germany.
J Cell Biochem. 2008 Feb 1;103(2):413-33. doi: 10.1002/jcb.21415.
The molecular events associated with the age-related gain of fatty tissue in human bone marrow are still largely unknown. Besides enhanced adipogenic differentiation of mesenchymal stem cells (MSCs), transdifferentiation of osteoblast progenitors may contribute to bone-related diseases like osteopenia. Transdifferentiation of MSC-derived osteoblast progenitors into adipocytes and vice versa has previously been proven feasible in our cell culture system. Here, we focus on mRNA species that are regulated during transdifferentiation and represent possible control factors for the initiation of transdifferentiation. Microarray analyses comparing transdifferentiated cells with normally differentiated cells exhibited large numbers of reproducibly regulated genes for both, adipogenic and osteogenic transdifferentiation. To evaluate the relevance of individual genes, we designed a scoring scheme to rank genes according to reproducibility, regulation level, and reciprocity between the different transdifferentiation directions. Thereby, members of several signaling pathways like FGF, IGF, and Wnt signaling showed explicitly differential expression patterns. Additional bioinformatic analysis of microarray analyses allowed us to identify potential key factors associated with transdifferentiation of adipocytes and osteoblasts, respectively. Fibroblast growth factor 1 (FGF1) was scored as one of several lead candidate gene products to modulate the transdifferentiation process and is shown here to exert inhibitory effects on adipogenic commitment and differentiation.
与人类骨髓中脂肪组织随年龄增长相关的分子事件在很大程度上仍不为人知。除了间充质干细胞（MSC）的成脂分化增强外，成骨祖细胞的转分化可能导致诸如骨质减少等骨相关疾病。此前已在我们的细胞培养系统中证实，MSC来源的成骨祖细胞可转分化为脂肪细胞，反之亦然。在此，我们聚焦于在转分化过程中受到调控且可能是转分化起始控制因素的mRNA种类。将转分化细胞与正常分化细胞进行比较的微阵列分析显示，对于成脂和成骨转分化，均有大量可重复调控的基因。为评估单个基因的相关性，我们设计了一种评分方案，根据不同转分化方向之间的可重复性、调控水平和互反性对基因进行排名。由此，FGF、IGF和Wnt信号等几种信号通路的成员呈现出明显的差异表达模式。对微阵列分析的额外生物信息学分析使我们能够分别鉴定与脂肪细胞和成骨细胞转分化相关的潜在关键因子。成纤维细胞生长因子1（FGF1）被评为调控转分化过程的几种主要候选基因产物之一，本文显示其对成脂定向分化和分化具有抑制作用。
