Sensory and Motor System Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1875-80. doi: 10.1073/pnas.1207458110. Epub 2013 Jan 14.
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 (RBPjκ) 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 RBPjκ 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 RBPjκ 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 RBPjκ-dependent Notch signaling in chondrocytes modulates the terminal stage of endochondral ossification and OA development, representing an extracellular therapeutic target of OA.
在这里，我们研究了 Notch 信号通路在软骨内骨化过程中的作用，软骨内骨化过程对于骨关节炎（OA）的发展至关重要。Notch1 和 Notch2 的细胞内结构域随着其在小鼠肢软骨和小鼠及人 OA 关节软骨中的分化而转移到软骨细胞的核内。在含有 Sry 框基因 9（Sox9）-Cre 的软骨祖细胞中，组织特异性地敲除 Notch 转录效应因子重组信号结合蛋白免疫球蛋白 k 轻链 J（RBPjκ），导致肢软骨中的软骨内骨化终末阶段受损。在正常骨骼生长后，使用 II 型胶原（Col2a1）-Cre（ERT）；Rbpj（fl/fl）小鼠通过注射他莫昔芬在成年关节软骨中敲除 RBPjκ，导致膝关节对 OA 发展的抵抗力增强。Notch 细胞内结构域与效应因子 RBPjκ 通过诱导软骨细胞中的靶基因 Hes1 刺激软骨内骨化。在 Notch 配体中，Jagged1 在 OA 发展过程中被强烈诱导。最后，向小鼠膝关节内注射小分子 Notch 抑制剂 N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-(S)-苯甘氨酸叔丁酯（DAPT），可预防 OA 的发展。软骨细胞中 RBPjκ 依赖性 Notch 信号通路调节软骨内骨化的终末阶段和 OA 的发展，是 OA 的一种细胞外治疗靶点。
