Yoon Byeong S, Pogue Robert, Ovchinnikov Dmitri A, Yoshii Isaac, Mishina Yuji, Behringer Richard R, Lyons Karen M
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.
Development. 2006 Dec;133(23):4667-78. doi: 10.1242/dev.02680. Epub 2006 Oct 25.
Bone morphogenetic protein (BMP) signaling pathways are essential regulators of chondrogenesis. However, the roles of these pathways in vivo are not well understood. Limb-culture studies have provided a number of essential insights, including the demonstration that BMP pathways are required for chondrocyte proliferation and differentiation. However, limb-culture studies have yielded contradictory results; some studies indicate that BMPs exert stimulatory effects on differentiation, whereas others support inhibitory effects. Therefore, we characterized the skeletal phenotypes of mice lacking Bmpr1a in chondrocytes (Bmpr1a(CKO)) and Bmpr1a(CKO);Bmpr1b+/- (Bmpr1a(CKO);1b+/-) in order to test the roles of BMP pathways in the growth plate in vivo. These mice reveal requirements for BMP signaling in multiple aspects of chondrogenesis. They also demonstrate that the balance between signaling outputs from BMP and fibroblast growth factor (FGF) pathways plays a crucial role in the growth plate. These studies indicate that BMP signaling is required to promote Ihh expression, and to inhibit activation of STAT and ERK1/2 MAPK, key effectors of FGF signaling. BMP pathways inhibit FGF signaling, at least in part, by inhibiting the expression of FGFR1. These results provide a genetic in vivo demonstration that the progression of chondrocytes through the growth plate is controlled by antagonistic BMP and FGF signaling pathways.
骨形态发生蛋白（BMP）信号通路是软骨形成的重要调节因子。然而，这些通路在体内的作用尚未完全明确。肢体培养研究提供了许多重要见解，包括证明BMP通路是软骨细胞增殖和分化所必需的。然而，肢体培养研究得出了相互矛盾的结果；一些研究表明BMP对分化具有刺激作用，而另一些研究则支持抑制作用。因此，我们对软骨细胞中缺乏Bmpr1a的小鼠（Bmpr1a(CKO)）以及Bmpr1a(CKO);Bmpr1b+/-（Bmpr1a(CKO);1b+/-）的骨骼表型进行了特征分析，以测试BMP通路在体内生长板中的作用。这些小鼠揭示了BMP信号在软骨形成多个方面的需求。它们还表明，BMP和成纤维细胞生长因子（FGF）通路信号输出之间的平衡在生长板中起着关键作用。这些研究表明，BMP信号传导对于促进Ihh表达以及抑制FGF信号传导的关键效应器STAT和ERK1/2 MAPK的激活是必需的。BMP通路至少部分地通过抑制FGFR1的表达来抑制FGF信号传导。这些结果提供了一个体内遗传学证据，表明软骨细胞通过生长板的进程受拮抗的BMP和FGF信号通路控制。
