University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
J Biol Chem. 2011 Nov 25;286(47):40575-83. doi: 10.1074/jbc.M111.274910. Epub 2011 Oct 10.
Fibroblast growth factor 2 (FGF2) positively modulates osteoblast differentiation and bone formation. However, the mechanism(s) is not fully understood. Because the Wnt canonical pathway is important for bone homeostasis, this study focuses on modulation of Wnt/β-catenin signaling using Fgf2(-/-) mice (FGF2 all isoforms ablated), both in the absence of endogenous FGF2 and in the presence of exogenous FGF2. This study demonstrates a role of endogenous FGF2 in bone formation through Wnt signaling. Specifically, mRNA expression for the canonical Wnt genes Wnt10b, Lrp6, and β-catenin was decreased significantly in Fgf2(-/-) bone marrow stromal cells during osteoblast differentiation. In addition, a marked reduction of Wnt10b and β-catenin protein expression was observed in Fgf2(-/-) mice. Furthermore, Fgf2(-/-) osteoblasts displayed marked reduction of inactive phosphorylated glycogen synthase kinase-3β, a negative regulator of Wnt/β-catenin pathway as well as a significant decrease of Dkk2 mRNA, which plays a role in terminal osteoblast differentiation. Addition of exogenous FGF2 promoted β-catenin nuclear accumulation and further partially rescued decreased mineralization in Fgf2(-/-) bone marrow stromal cell cultures. Collectively, our findings suggest that FGF2 stimulation of osteoblast differentiation and bone formation is mediated in part by modulating the Wnt pathway.
成纤维细胞生长因子 2（FGF2）正向调节成骨细胞分化和骨形成。然而，其机制尚不完全清楚。由于 Wnt 经典途径对骨稳态很重要，因此本研究使用 Fgf2（-/-）小鼠（所有 FGF2 同种型缺失）聚焦于 Wnt/β-catenin 信号的调节，包括内源性 FGF2 缺失和外源性 FGF2 存在的情况。本研究证明了内源性 FGF2 通过 Wnt 信号在骨形成中的作用。具体而言，在成骨细胞分化过程中，Fgf2（-/-）骨髓基质细胞中经典 Wnt 基因 Wnt10b、Lrp6 和 β-catenin 的 mRNA 表达显著降低。此外，在 Fgf2（-/-）小鼠中观察到 Wnt10b 和 β-catenin 蛋白表达明显减少。此外，Fgf2（-/-）成骨细胞中失活的磷酸化糖原合成酶激酶-3β（Wnt/β-catenin 途径的负调节剂）的表达显著减少，以及 Dkk2 mRNA 的表达显著减少，这在成骨细胞终末分化中起作用。添加外源性 FGF2 可促进β-catenin 核积累，并进一步部分挽救 Fgf2（-/-）骨髓基质细胞培养物中矿化减少的情况。总之，我们的研究结果表明，FGF2 刺激成骨细胞分化和骨形成是通过调节 Wnt 途径来介导的。
