Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton
Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton
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DOI：
10.1242/dev.01006
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发表时间：
2004-03-01
期刊：
影响因子：
4.6
通讯作者：
McMahon, AP
中科院分区：
文献类型：
--
作者：
Long, FX;Chung, UI;McMahon, AP
印度刺猬（Ihh）对软骨内骨骼成骨细胞谱系的发育是不可或缺的。为了确定Ihh是否直接需要成骨细胞分化，我们通过基因操纵smoothened (Smo)，其编码一种跨膜蛋白，该蛋白对所有Hedgehog （Hh）信号的转导至关重要。通过Cre-LoxP方法从软骨膜细胞中去除Smo可阻止正常骨颈的形成，也可消除原发性海绵的发育。对野生型和Smo（n/n）细胞组成的嵌合胚胎的分析表明，Smo（n/n）细胞不能在骨颈或原代海绵中形成成骨细胞，而是产生异位软骨细胞。为了评估Ihh是否足以在体内诱导骨形成，我们分析了胚胎长骨中的骨颈，其中Ihh通过UAS-GAL4基因系统在所有软骨细胞中人工表达。尽管异位Ihh不会沿整个软骨基底诱导明显的骨化，但它会促进骨颈向骨骺的进展，这表明异位Ihh与骨形态发生蛋白（BMPs）等内源性因子之间存在协同作用。与该模型一致，Hh信号进一步被发现在bmp诱导的肢体芽细胞系的成骨过程中是必需的。综上所述，这些结果表明，在发育中的长骨中，Ihh信号是成骨细胞谱系所直接需要的，并且Ihh与其他因子（如bmp）一起起作用，诱导成骨细胞分化。我们认为Ihh在体内作用于潜在的祖细胞，促进成骨细胞并阻止软骨细胞分化。
Indian hedgehog (Ihh) is indispensable for development of the osteoblast lineage in the endochondral skeleton. In order to determine whether Ihh is directly required for osteoblast differentiation, we have genetically manipulated smoothened (Smo), which encodes a transmembrane protein that is essential for transducing all Hedgehog (Hh) signals. Removal of Smo from perichondrial cells by the Cre-LoxP approach prevents formation of a normal bone collar and also abolishes development of the primary spongiosa. Analysis of chimeric embryos composed of wildtype and Smo(n/n) cells indicates that Smo(n/n) cells fail to contribute to osteoblasts in either the bone collar or the primary spongiosa but generate ectopic chondrocytes. In order to assess whether Ihh is sufficient to induce bone formation in vivo, we have analyzed the bone collar in the long bones of embryos in which Ihh was artificially expressed in all chondrocytes by the UAS-GAL4 bigenic system. Although ectopic Ihh does not induce overt ossification along the entire cartilage anlage, it promotes progression of the bone collar toward the epiphysis, suggesting a synergistic effect between ectopic Ihh and endogenous factors such as the bone morphogenetic proteins (BMPs). In keeping with this model, Hh signaling is further found to be required in BMP-induced osteogenesis in cultures of a limb-bud cell line. Taken together, these results demonstrate that Ihh signaling is directly required for the osteoblast lineage in the developing long bones and that Ihh functions in conjunction with other factors such as BMPs to induce osteoblast differentiation. We suggest that Ihh acts in vivo on a potential progenitor cell to promote osteoblast and prevent chondrocyte differentiation.