The Effects of Indian Hedgehog Deletion on Mesenchyme Cells: Inducing Intermediate Cartilage Scaffold Ossification to Cause Growth Plate and Phalange Joint Absence, Short Limb, and Dwarfish Phenotypes
The Effects of Indian Hedgehog Deletion on Mesenchyme Cells: Inducing Intermediate Cartilage Scaffold Ossification to Cause Growth Plate and Phalange Joint Absence, Short Limb, and Dwarfish Phenotypes
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印度刺猬缺失对间充质细胞的影响：诱导中间软骨支架骨化导致生长板和指骨关节缺失、短肢和侏儒表型
DOI：
10.1089/scd.2018.0071
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发表时间：
2018-10-01
影响因子：
4
通讯作者：
Wei, Lei
中科院分区：
文献类型：
--
作者：
Sun, Jian;Wei, Xiaochun;Wei, Lei
软骨内成骨在脊椎动物肢体发育和骨骼动态平衡中起着至关重要的作用，肢体间充质细胞形成中间软骨支架，发育成生长板，然后被骨取代。虽然已知印度刺猬(IHH)控制软骨细胞的肥大分化过程，但其从间充质细胞到软骨形成早期的作用尚不清楚。为了确定IHH在间充质细胞软骨形成早期阶段的功能，我们使用PrX1-Cre；IHH(fl/fl)；rosa26(-ZsGreen1)小鼠，在E9.5的PRX1-Cre；IHH(fl/fl)；rosa26(-ZsGreen1)小鼠中特异性地删除了PRX1表达的间充质细胞中的IHH。我们发现，缺失间充质细胞中的IHH会导致中间软骨支架早期和快速的骨化，导致生长板和指骨关节缺失，四肢短小和矮小。从缺失的IHH间充质细胞获得的绿色荧光蛋白(GFP)阳性细胞与von Kossa和骨钙素阳性染色区域重叠。这些从Prx1-Cre、IHH(fl/fl)、rosa26(-ZsGreen1)新生小鼠分离的缺失的IHH/GFP阳性细胞通过茜素红和von Kossa染色阳性以及Col1a1、骨钙素和Runx2表达的增强而成骨分化。我们的研究结果表明，在肢体发育早期删除间充质细胞中的IHH可以促进中间软骨支架的骨化，从而防止生长板的形成，从而导致指骨关节缺失、肢体短小和侏儒表型。
The endochondral ossification plays a critical role in vertebrate limb development and skeletal homeostasis, where limb mesenchyme cells form an intermediate cartilage scaffold that develops into growth plates and then replaced by bone. Although Indian hedgehog (Ihh) is known to control the hypertrophic differentiation process of chondrocytes, its role from the mesenchyme cells to the early stages of chondrogenesis is unclear. To define the function of Ihh in the mesenchymal cell's early stages of chondrogenesis, we specifically delete Ihh in Prx1-expressed mesenchyme cells at E9.5 using Prx1-Cre;Ihh(fl/fl);Rosa26(-ZsGreen1) mice. We found that deleting Ihh in the mesenchyme cells results in an early and quick ossification of the intermediate cartilage scaffold, causing the growth plate and phalange joint absence, short limbs, and dwarfishness. The green fluorescent protein (GFP)-positive cells derived from deleted Ihh mesenchyme cells overlap with von Kossa- and osteocalcin-positive staining area. These deleted Ihh/GFP-positive cells isolated from Prx1-Cre;Ihh(fl/fl);Rosa26(-ZsGreen1) newborn mice had osteogenic differentiation by showing a positive Alizarin red and von Kossa staining, as well as an enhanced Col1a1, osteocalcin, and Runx2 expression. Our findings demonstrate that deleting Ihh in mesenchyme cells during early limb development promotes intermediate cartilage scaffold ossification, which prevents growth plate formation that causes phalange joint absence, short limb, and dwarfish phenotype.