Pathi S, Rutenberg J B, Johnson R L, Vortkamp A
Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts, 02115, USA.
Dev Biol. 1999 May 15;209(2):239-53. doi: 10.1006/dbio.1998.9181.
Bone morphogenetic proteins (BMPs) have been implicated in regulating multiple stages of bone development. Recently it has been shown that constitutive activation of the BMP receptor-IA blocks chondrocyte differentiation in a similar manner as misexpression of Indian hedgehog. In this paper we analyze the role of BMPs as possible mediators of Indian hedgehog signaling and use Noggin misexpression to gain insight into additional roles of BMPs during cartilage differentiation. We show by comparative analysis of BMP and Ihh expression domains that the borders of Indian hedgehog expression in the chondrocytes are reflected in changes of the expression level of several BMP genes in the adjacent perichondrium. We further demonstrate that misexpression of Indian hedgehog appears to directly upregulate BMP2 and BMP4 expression, independent of the differentiation state of the flanking chondrocytes. In contrast, changes in BMP5 and BMP7 expression in the perichondrium correspond to altered differentiation states of the flanking chondrocytes. In addition, Noggin and Chordin, which are both expressed in the developing cartilage elements, also change their expression pattern after Ihh misexpression. Finally, we use retroviral misexpression of Noggin, a potent antagonist of BMP signaling, to gain insight into additional roles of BMP signaling during cartilage differentiation. We find that BMP signaling is necessary for the growth and differentiation of the cartilage elements. In addition, this analysis revealed that the members of the BMP/Noggin signaling pathway are linked in a complex autoregulatory network.
骨形态发生蛋白（BMPs）参与调节骨骼发育的多个阶段。最近研究表明，BMP受体-IA的组成性激活以类似于印度刺猬蛋白（Ihh）错误表达的方式阻断软骨细胞分化。在本文中，我们分析了BMPs作为Ihh信号可能介导者的作用，并利用Noggin的错误表达来深入了解BMPs在软骨分化过程中的其他作用。通过对BMP和Ihh表达域的比较分析，我们发现软骨细胞中Ihh表达的边界反映在相邻软骨膜中几个BMP基因表达水平的变化上。我们进一步证明，Ihh的错误表达似乎直接上调BMP2和BMP4的表达，而与侧翼软骨细胞的分化状态无关。相比之下，软骨膜中BMP5和BMP7表达的变化与侧翼软骨细胞分化状态的改变相对应。此外，在发育中的软骨成分中均有表达的Noggin和Chordin，在Ihh错误表达后也改变了它们的表达模式。最后，我们利用BMP信号的强效拮抗剂Noggin的逆转录病毒错误表达，来深入了解BMP信号在软骨分化过程中的其他作用。我们发现BMP信号对于软骨成分的生长和分化是必需的。此外，该分析揭示了BMP/Noggin信号通路的成员在一个复杂的自调节网络中相互关联。
