Canonical FGFs Prevent Osteogenic Lineage Commitment and Differentiation of Human Bone Marrow Stromal Cells Via ERK1/2 Signaling
Canonical FGFs Prevent Osteogenic Lineage Commitment and Differentiation of Human Bone Marrow Stromal Cells Via ERK1/2 Signaling
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DOI：
10.1002/jcb.25631
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发表时间：
2017-02
影响因子：
4
通讯作者：
M. Simann;S. Le Blanc;Verena Schneider;V. Zehe;M. Lüdemann;N. Schütze;F. Jakob;T. Schilling
中科院分区：
文献类型：
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作者：
M. Simann;S. Le Blanc;Verena Schneider;V. Zehe;M. Lüdemann;N. Schütze;F. Jakob;T. Schilling
控制骨小梁人骨髓基质细胞（hBMSCs）的脂肪-成骨谱系决定，有利于成骨，是骨质疏松症治疗和预防的一种有前途的方法。以前，成纤维细胞生长因子1（FGF 1）及其亚家族成员FGF 2被评为主要候选人行使控制骨骼前体承诺和谱系决定，尽管文献结果是高度不一致的。我们发现FGF 1和FGF 2强烈阻止hBMSCs的成骨承诺和分化。细胞外基质（ECM）的矿化和成骨标志物基因碱性磷酸酶（ALP）、胶原蛋白1A 1（COL 1A 1）和整合素结合唾液蛋白（IBSP）的mRNA表达显著降低。此外，成骨定型的主要调节因子如Runt相关转录因子2（RUNX 2）和骨形态发生蛋白4（BMP 4）下调。当在成脂培养条件下给药时，典型FGF不支持成骨标志物表达。此外，尽管存在成骨分化因子，FGF甚至使预分化脂肪细胞的促成骨谱系决定失效。与FGF受体2（FGFR 2）相反，FGFR 1在成骨和成脂分化以及FGF添加过程中稳定表达。此外，发现FGFR 1和细胞外信号调节激酶1和2（ERK 1/2）负责使用相应抑制剂的潜在信号转导。总之，我们提出了新的发现，表明经典的FGFR-ERK 1/2信号转导将hBMSC捕获在预定型状态，并阻止了定型前体的进一步成熟。我们的研究结果可能有助于解开和控制与衰老相关的异常脂肪生成相关的检查点，从而治疗退行性疾病，如骨质疏松症和骨骼组织工程策略。J.细胞。118：263-275，2017.© 2016 Wiley Periodicals，Inc.
Controlling the adipo‐osteogenic lineage decision of trabecular human bone marrow stromal cells (hBMSCs) in favor of osteogenesis represents a promising approach for osteoporosis therapy and prevention. Previously, Fibroblast Growth Factor 1 (FGF1) and its subfamily member FGF2 were scored as leading candidates to exercise control over skeletal precursor commitment and lineage decision albeit literature results are highly inconsistent. We show here that FGF1 and 2 strongly prevent the osteogenic commitment and differentiation of hBMSCs. Mineralization of extracellular matrix (ECM) and mRNA expression of osteogenic marker genes Alkaline Phosphatase (ALP), Collagen 1A1 (COL1A1), and Integrin‐Binding Sialoprotein (IBSP) were significantly reduced. Furthermore, master regulators of osteogenic commitment like Runt‐Related Transcription Factor 2 (RUNX2) and Bone Morphogenetic Protein 4 (BMP4) were downregulated. When administered under adipogenic culture conditions, canonical FGFs did not support osteogenic marker expression. Moreover despite the presence of osteogenic differentiation factors, FGFs even disabled the pro‐osteogenic lineage decision of pre‐differentiated adipocytic cells. In contrast to FGF Receptor 2 (FGFR2), FGFR1 was stably expressed throughout osteogenic and adipogenic differentiation and FGF addition. Moreover, FGFR1 and Extracellular Signal‐Regulated Kinases 1 and 2 (ERK1/2) were found to be responsible for underlying signal transduction using respective inhibitors. Taken together, we present new findings indicating that canonical FGFR‐ERK1/2 signaling entrapped hBMSCs in a pre‐committed state and arrested further maturation of committed precursors. Our results might aid in unraveling and controlling check points relevant for ageing‐associated aberrant adipogenesis with consequences for the treatment of degenerative diseases such as osteoporosis and for skeletal tissue engineering strategies. J. Cell. Biochem. 118: 263–275, 2017. © 2016 Wiley Periodicals, Inc.