Nature Medicine：Notch蛋白对形成骨和力量起关键作用
美国科学家近日研究发现，指导胚胎细胞分化的蛋白Notch对于人体骨和力量的形成起着关键作用。这一发现有助于为骨质疏松症等疾病提供更基础的认识。相关论文2月24日在线发表于《自然—医学》（Nature Medicine）上。
领导此次研究的是美国贝勒医学院的Brendan Lee教授。他表示，Notch刺激了造骨细胞（osteoblastic cells）的早期分化。而当敲除小鼠这些细胞中Notch的功能后，研究人员发现了骨质疏松症或骨的损失，与上了年纪的人的骨质疏松症类似。
进一步的研究发现，敲除Notch后，造骨细胞能正常工作，但是破骨细胞（osteoclasts，主要功能是重吸收或移动骨质）的活性无法得到有效调节。研究人员表示，许多患有骨质疏松症的女性实际上遭遇的是类似的问题，即骨形成与骨重吸收之间的不平衡。结果是，虽然形成了足够的骨，但是重吸收的速率却反常地高，从而无法维持一个健康的骨骼。
研究人员表示，将来的研究将着重关注Notch功能的丧失对造骨细胞和破骨细胞间信号通路的干扰。这也意味着，Notch蛋白和相关细胞路径或许可作为药靶，以治疗某些类型的骨病。
生物谷推荐原始出处：
Nature Medicine
Published online: 24 February 2008 | doi:10.1038/nm1712
Dimorphic effects of Notch signaling in bone homeostasis
Feyza Engin1, Zhenqiang Yao2,6, Tao Yang1,6, Guang Zhou1, Terry Bertin1, Ming Ming Jiang1,3, Yuqing Chen1,3, Lisa Wang4, Hui Zheng1, Richard E Sutton5, Brendan F Boyce2 & Brendan Lee1,3
Abstract
Notch signaling is a key mechanism in the control of embryogenesis. However, its in vivo function during mesenchymal cell differentiation, and, specifically, in bone homeostasis, remains largely unknown. Here, we show that osteoblast-specific gain of Notch function causes severe osteosclerosis owing to increased proliferation of immature osteoblasts. Under these pathological conditions, Notch stimulates early osteoblastic proliferation by upregulating the genes encoding cyclin D, cyclin E and Sp7 (osterix). The intracellular domain of Notch1 also regulates terminal osteoblastic differentiation by directly binding Runx2 and repressing its transactivation function. In contrast, loss of all Notch signaling in osteoblasts, generated by deletion of the genes encoding presenilin-1 and presenilin-2 in bone, is associated with late-onset, age-related osteoporosis, which in turn results from increased osteoblast-dependent osteoclastic activity due to decreased osteoprotegerin mRNA expression in these cells. Together, these findings highlight the potential dimorphic effects of Notch signaling in bone homeostasis and may provide direction for novel therapeutic applications.
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