Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development
Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development
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DOI：
10.1073/pnas.1207458110
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发表时间：
2013-01-29
影响因子：
11.1
通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
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作者：
Hosaka, Yoko;Saito, Taku;Kawaguchi, Hiroshi
在这里，我们研究了Notch信号在软骨内骨化过程中的参与，这对骨关节炎（OA）的发展至关重要。Notch 1和Notch 2的细胞内结构域移位到软骨细胞的细胞核中，并在小鼠肢体软骨以及小鼠和人OA关节软骨中分化。在含有SRY盒基因9（Sox 9）-Cre; Rbpj（fl/fl）小鼠胚胎的软骨祖细胞中，IG kappa J（RBPj kappa）的Notch转录效应物重组信号结合蛋白的组织特异性失活导致肢体软骨中软骨内骨化的终末阶段受损。使用II型胶原（Col 2a 1）-Cre（ERT）;Rbpj（fl/fl）小鼠通过他莫昔芬注射在正常骨骼生长后的成年关节软骨中的RBPj κ失活引起对膝关节中OA发展的抵抗。Notch细胞内结构域与效应RBPj κ刺激软骨内骨化通过诱导软骨细胞中的靶基因Hes 1。在Notch配体中，Jagged 1在OA发展过程中被强烈诱导。最后，关节内注射N-[N-（3，5-二氟苯乙酸酯）-L-丙氨酰]-（S）-苯基甘氨酸叔丁酯（DAPT），一种小的化合物Notch抑制剂，小鼠膝关节，防止OA的发展。软骨细胞中的RBPj κ依赖性Notch信号调节软骨内骨化和OA发展的终末阶段，代表OA的细胞外治疗靶点。
Here we examined the involvement of Notch signaling in the endochondral ossification process, which is crucial for osteoarthritis (OA) development. Intracellular domains of Notch1 and -2 were translocated into the nucleus of chondrocytes with their differentiation in mouse limb cartilage and in mouse and human OA articular cartilage. A tissue-specific inactivation of the Notch transcriptional effector recombination signal binding protein for Ig kappa J (RBPj kappa) in chondroprogenitor cells of SRY-box containing gene 9 (Sox9)-Cre; Rbpj(fl/fl) mouse embryos caused an impaired terminal stage of endochondral ossification in the limb cartilage. The RBPj kappa inactivation in adult articular cartilage after normal skeletal growth using type II collagen (Col2a1)-Cre(ERT);Rbpj(fl/fl) mice by tamoxifen injection caused resistance to OA development in the knee joint. Notch intracellular domain with the effector RBPj kappa stimulated endochondral ossification through induction of the target gene Hes1 in chondrocytes. Among the Notch ligands, Jagged1 was strongly induced during OA development. Finally, intraarticular injection of N-[N-(3,5-diflurophenylacetate)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT), a small compound Notch inhibitor, to the mouse knee joint prevented OA development. The RBPj kappa-dependent Notch signaling in chondrocytes modulates the terminal stage of endochondral ossification and OA development, representing an extracellular therapeutic target of OA.