Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes
Discoidin domain receptor 1 regulates endochondral ossification through terminal differentiation of chondrocytes
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DOI：
10.1096/fj.201901852rr
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发表时间：
2020-03-03
期刊：
影响因子：
4.8
通讯作者：
Wang, Chau-Zen
中科院分区：
文献类型：
--
作者：
Chou, Liang-Yin;Chen, Chung-Hwan;Wang, Chau-Zen
生长板中的软骨细胞负责软骨内骨化过程中长骨的纵向生长。盘状结构域受体1（Ddr 1）在软骨细胞中表达，但在软骨内骨化过程中DDR 1调节软骨细胞行为的分子机制仍不清楚。为了阐明Ddr 1介导的软骨细胞功能，我们在这项研究中产生了软骨细胞特异性Ddr 1敲除（CKO Delta Ddr 1）小鼠。CKO Delta Ddr 1小鼠显示次级骨化中心发育延迟，后肢生长板长度增加。在CKO Delta Ddr 1小鼠的胫骨生长板中，增殖区的软骨细胞增殖减少，并且软骨细胞中Ihh、MMP 13和Col-X表达的显著下调导致肥大区的终末分化减少。此外，CKO Delta Ddr 1小鼠生长板中的凋亡软骨细胞减少。我们的结论是，Ddr 1基因敲除的软骨细胞在生长板中表现出增殖、终末分化和凋亡的减少，这延迟了软骨内骨化并导致身材矮小。我们还证明了Ddr 1调节Ihh/Gli 1/Gli 2/Col-X通路来调节软骨细胞终末分化。这些结果表明，Ddr 1是所需的软骨细胞调节内软骨骨化骨骼发育。
Chondrocytes in growth plates are responsible for longitudinal growth in long bones during endochondral ossification. Discoidin domain receptor 1 (Ddr1) is expressed in chondrocytes, but the molecular mechanisms by which DDR1 regulates chondrocyte behaviors during the endochondral ossification process remain undefined. To elucidate Ddr1-mediate chondrocyte functions, we generated chondrocyte-specific Ddr1 knockout (CKO Delta Ddr1) mice in this study. The CKO Delta Ddr1 mice showed delayed development of the secondary ossification center and increased growth plate length in the hind limbs. In the tibial growth plate in CKO Delta Ddr1 mice, chondrocyte proliferation was reduced in the proliferation zone, and remarkable downregulation of Ihh, MMP13, and Col-X expression in chondrocytes resulted in decreased terminal differentiation in the hypertrophic zone. Furthermore, apoptotic chondrocytes were reduced in the growth plates of CKO Delta Ddr1 mice. We concluded that chondrocytes with Ddr1 knockout exhibit decreased proliferation, terminal differentiation, and apoptosis in growth plates, which delays endochondral ossification and results in short stature. We also demonstrated that Ddr1 regulates the Ihh/Gli1/Gli2/Col-X pathway to regulate chondrocyte terminal differentiation. These results indicate that Ddr1 is required for chondrocytes to regulate endochondral ossification in skeletal development.