Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
J Bone Miner Res. 2010 Oct;25(10):2175-83. doi: 10.1002/jbmr.115.
Osteosclerosis is a pathologic bone disease characterized by an increase in bone formation over bone resorption. Genetic factors that contribute to the pathogenesis of this disease are poorly understood. Dysregulation or mutation in many components of the Notch signaling pathway results in a wide range of human developmental disorders and cancers, including bone diseases. Our previous study found that activation of the Notch signaling in osteoblasts promotes cell proliferation and inhibits differentiation, leading to an osteosclerotic phenotype in transgenic mice. In this study we report a longer-lived mouse model that also develops osteosclerosis and a genetic manipulation that completely rescues the phenotype. Conditionally cre-activated expression of Notch1 intracellular domain (NICD) in vivo exclusively in committed osteoblasts caused massive osteosclerosis with growth retardation and abnormal vertebrae. Importantly, selective deletion of a Notch nuclear effector--Rbpj--in osteoblasts completely suppressed the osteosclerotic and growth-retardation phenotypes. Furthermore, cellular and molecular analyses of bones from the rescued mice confirmed that NICD-dependent molecular alterations in osteoblasts were completely reversed by removal of the Rbpj pathway. Together, our observations show that the osteosclerosis owing to activation of Notch signaling in osteoblasts is canonical in nature because it depends solely on Rbpj signaling. As such, it identifies Rbpj as a specific target for manipulating Notch signaling in a cell-autonomous fashion in osteoblasts in bone diseases where Notch may be dysregulated.
骨质硬化症是一种以骨形成增加超过骨吸收为特征的病理性骨疾病。导致这种疾病发生的遗传因素还了解甚少。 Notch 信号通路的许多成分的失调或突变会导致广泛的人类发育障碍和癌症，包括骨疾病。我们之前的研究发现，成骨细胞中 Notch 信号的激活会促进细胞增殖并抑制分化，导致转基因小鼠出现骨质硬化表型。在这项研究中，我们报告了一个寿命更长的小鼠模型，该模型也会发展出骨质硬化症，并且通过遗传操作完全挽救了表型。体内条件性 cre 激活 Notch1 细胞内结构域（NICD）的表达仅在成骨细胞中特异性表达，导致大量骨质硬化症、生长迟缓以及异常的椎体。重要的是，在成骨细胞中选择性删除 Notch 核效应物——Rbpj——完全抑制了骨质硬化和生长迟缓表型。此外，对挽救小鼠的骨骼进行的细胞和分子分析证实，通过去除 Rbpj 途径，NICD 依赖性的成骨细胞分子改变被完全逆转。总之，我们的观察结果表明，由于成骨细胞中 Notch 信号的激活而导致的骨质硬化症在性质上是典型的，因为它仅依赖于 Rbpj 信号。因此，它将 Rbpj 鉴定为在 Notch 可能失调的骨疾病中成骨细胞中以细胞自主方式操纵 Notch 信号的特定靶标。
