Osteosclerosis owing to Notch gain of function is solely Rbpj-dependent.
Osteosclerosis owing to Notch gain of function is solely Rbpj-dependent.
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DOI：
10.1002/jbmr.115
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发表时间：
2010-10
影响因子：
6.2
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Tao, Jianning;Chen, Shan;Yang, Tao;Dawson, Brian;Munivez, Elda;Bertin, Terry;Lee, Brendan
骨硬化是一种病理性骨病，其特征是骨形成增加超过骨吸收。导致这种疾病发病机制的遗传因素知之甚少。 Notch 信号通路许多成分的失调或突变会导致多种人类发育障碍和癌症，包括骨病。我们之前的研究发现，成骨细胞中Notch信号的激活可促进细胞增殖并抑制分化，从而导致转基因小鼠出现骨硬化表型。在本研究中，我们报告了一种寿命较长的小鼠模型，该模型也出现骨硬化症，并且通过基因操作完全挽救了表型。 Notch1细胞内结构域（NICD）在体内条件性cre激活表达仅在定型成骨细胞中引起大规模骨硬化，伴有生长迟缓和椎骨异常。重要的是，成骨细胞中Notch核效应子Rbpj的选择性缺失完全抑制了骨硬化和生长迟缓表型。此外，对获救小鼠骨骼的细胞和分子分析证实，通过去除 Rbpj 通路，成骨细胞中 NICD 依赖性分子改变被完全逆转。总之，我们的观察表明，由于成骨细胞中 Notch 信号激活引起的骨硬化本质上是典型的，因为它仅依赖于 Rbpj 信号。因此，它将 Rbpj 确定为在 Notch 可能失调的骨疾病中以细胞自主方式操纵 Notch 信号传导的特定靶标。
Osteosclerosis is a pathological 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 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 the present 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 due to activation of Notch signaling in osteoblasts is canonical in nature since 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.
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