Bone morphogenetic protein signals are required for cartilage formation and differently regulate joint development during skeletogenesis
Bone morphogenetic protein signals are required for cartilage formation and differently regulate joint development during skeletogenesis
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DOI：
10.1359/jbmr.2002.17.5.898
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发表时间：
2002-05-01
影响因子：
6.2
通讯作者：
Yoshikawa, H
中科院分区：
文献类型：
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作者：
Tsumaki, N;Nakase, T;Yoshikawa, H
骨形态发生蛋白(BMP)家族由大量成员组成，在发育过程中具有多种生物学活性。各种组织表达胸膜BMP家族成员，它们似乎协同调节发育事件。在这里，软骨细胞中的多个BMP信号被失活，以阐明BMP在骨骼形成过程中的功能。为了获得组织特异性失活，在α2(XI)胶原基因(Col11a2)启动子/增强子序列的控制下，Noggin基因在软骨中过表达。由此产生的转基因小鼠缺乏大部分软骨成分，这表明没有BMP信号，软骨就不会发育。这些效应似乎是通过下调Sox9的表达来实现的。相反，通过在软骨中靶向表达Bmp4来激活骨骼中特定的BMP信号，并将所产生的表型与表达BMP家族另一成员生长和分化因子-5(GDF-5)的转基因小鼠的表型进行比较。与GDF5的表达一样，Bmp4在骨骼中的过度活动导致软骨产量的增加和软骨细胞的分化，但不像GDF5那样干扰关节的形成。在骨骼形成过程中，每个BMP的独特作用可能存在于关节发育的调节中。在Noggin转基因小鼠中，除了Bmp4和GDF5过度激活对软骨过度生产的共同影响外，多个BMPs失活导致的软骨丢失表明，多个BMPs单独增强了软骨产生的信号。这些结论可能解释了多个BMP在软骨中共表达的原因。
The bone morphogenetic protein (BMP) family consists of a large number of members and has diverse biological activities during development. Various tissues express pleural BMP family members, which seem to cooperatively regulate developmental events. Here, multiple BMP signals were inactivated in chondrocytes to clarify the function of BMPs during skeletogenesis. To obtain tissue-specific inactivation, Noggin gene (Nog) was overexpressed in cartilage under the control of alpha2(XI) collagen gene (Col11a2) promoter/enhancer sequences. The resultant transgenic mice lacked most of their cartilaginous components, suggesting that cartilage does not develop without BMP signals. These effects seem to be mediated through down-regulation of Sox9 expression. Conversely, specific BMP signals were activated in the skeleton by targeted expression of Bmp4 in cartilage and the resultant phenotype was compared with that of transgenic mice expressing growth and differentiation factor-5 (GDF-5), another BMP family member. Overactivity of Bmp4 in the skeleton caused an increase of cartilage production and enhanced chondrocyte differentiation, as GDF5 expression did, but it did not disturb joint formation as GDF5 did. During skeletogenesis, unique roles of each BMP may reside in the regulation of joint development. Together with the common effect on the cartilage overproduction by Bmp4 and GDF5 overactivation, loss of cartilage by inactivation of multiple BMPs in Noggin transgenic mice indicates that signals for cartilage production are reinforced by multiple BMPs exclusively. These conclusions may account for the reason why multiple BMPs are coexpressed in cartilage.