BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways
BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways
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DOI：
10.1242/dev.02680
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发表时间：
2006-12-01
期刊：
影响因子：
4.6
通讯作者：
Lyons, Karen M.
中科院分区：
文献类型：
--
作者：
Yoon, Byeong S.;Pogue, Robert;Lyons, Karen M.
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，这些途径在体内的作用还不清楚。肢体培养研究提供了许多重要的见解，包括证明BMP途径是软骨细胞增殖和分化所必需的。然而，肢体培养研究产生了矛盾的结果，一些研究表明，骨形成蛋白发挥刺激作用的分化，而其他支持抑制作用。因此，我们表征了软骨细胞中缺乏Bmpr 1a（Bmpr 1a（CKO））和Bmpr 1a（CKO）; Bmpr 1b（+/-）（Bmpr 1a（CKO）; 1b（+/-））的小鼠的骨骼表型，以测试BMP途径在体内生长板中的作用。这些小鼠揭示了软骨形成的多个方面对BMP信号传导的需求。他们还证明，BMP和成纤维细胞生长因子（FGF）途径的信号输出之间的平衡在生长板中起着至关重要的作用。这些研究表明，BMP信号需要促进Ihh表达，并抑制STAT和ERK 1/2 MAPK的激活，FGF信号的关键效应。BMP途径通过抑制FGFR 1的表达来至少部分地抑制FGF信号传导。这些结果提供了体内遗传学证明，软骨细胞通过生长板的进展是由拮抗性BMP和FGF信号通路控制的。
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.