BMP signaling stimulates cellular differentiation at multiple steps during cartilage development
BMP signaling stimulates cellular differentiation at multiple steps during cartilage development
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DOI：
10.1073/pnas.0503617102
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发表时间：
2005-12-13
影响因子：
11.1
通讯作者：
Kronenberg, HM
中科院分区：
文献类型：
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作者：
Kobayashi, T;Lyons, KM;Kronenberg, HM
骨形态发生蛋白（BMP）在软骨内成骨的多个阶段发挥重要作用。然而，BMP信号在体内软骨细胞中的作用仍然存在争议。在本研究中，我们过表达的组成型活性的BMP受体1A（caBmpr 1a）在软骨细胞通过使用两个系统：caBmpr 1a是直接驱动的大鼠II型胶原启动子在常规的转基因系统和间接驱动的UAS-Gal 4二元系统。CaBmpr 1a的表达引起的柱状层的增殖软骨细胞和成熟标志物的上调缩短，这表明加速分化的增殖软骨细胞向肥大软骨细胞。除了软骨细胞分化的加速，传统的转基因小鼠表现出扩大的软骨元素和形态学改变的软骨膜细胞，可能是由于前软骨细胞的分化刺激。此外，双基因表达的caBmpr 1a挽救了Bmpr 1b-空指骨的前软骨细胞的分化缺陷。这一发现表明，BMP信号是必要的指骨prechondrogenic细胞分化成软骨细胞和BMP受体1B的信号在这种情况下是由一个组成型活性的BMP受体1A取代。这些结果表明，BMP信号在前软骨细胞和生长板软骨细胞刺激他们的软骨细胞分化和成熟，分别向肥大。
Bone morphogenetic proteins (BMPs) play important roles at multiple stages of endochondral bone formation. However, the roles of BMP signaling in chondrocytes in vivo are still contentious. In the present study, we overexpressed a constitutively active BMP receptor 1A (caBmpr1a) in chondrocytes by using two systems: caBmpr1a was directly driven by a rat type II collagen promoter in a conventional transgenic system and indirectly driven in a UAS-Gal4 binary system. CaBmpr1a expression caused shortening of the columnar layer of proliferating chondrocytes and up-regulation of maturation markers, suggesting acceleration of differentiation of proliferating chondrocytes toward hypertrophic chondrocytes. In addition to the acceleration of chondrocyte differentiation, conventional transgenic mice showed widening of cartilage elements and morphological alteration of perichondrial cells, possibly due to stimulation of differentiation of prechondrogenic cells. Moreover, bigenic expression of caBmpr1a rescued the differentiation defect of prechondrogenic cells in Bmpr1b-null phalanges. This finding indicates that BMP signaling is necessary for phalangeal prechondrogenic cells to differentiate into chondrocytes and that signaling of BMP receptor 1B in this context is replaceable by that of a constitutively active BMP receptor 1A. These results suggest that BMP signaling in prechondrogenic cells and in growth plate chondrocytes stimulates their chondrocytic differentiation and maturation toward hypertrophy, respectively.