美國科學(xué)家近日研究發(fā)現(xiàn),，指導(dǎo)胚胎細胞分化的蛋白Notch對于人體骨和力量的形成起著關(guān)鍵作用,。這一發(fā)現(xiàn)有助于為骨質(zhì)疏松癥等疾病提供更基礎(chǔ)的認(rèn)識,。相關(guān)論文2月24日在線發(fā)表于《自然—醫(yī)學(xué)》（Nature Medicine）上,。
領(lǐng)導(dǎo)此次研究的是美國貝勒醫(yī)學(xué)院的Brendan Lee教授,。他表示,，Notch刺激了造骨細胞（osteoblastic cells）的早期分化,。而當(dāng)敲除小鼠這些細胞中Notch的功能后,，研究人員發(fā)現(xiàn)了骨質(zhì)疏松癥或骨的損失，與上了年紀(jì)的人的骨質(zhì)疏松癥類似,。
進一步的研究發(fā)現(xiàn),，敲除Notch后，造骨細胞能正常工作,，但是破骨細胞（osteoclasts,，主要功能是重吸收或移動骨質(zhì)）的活性無法得到有效調(diào)節(jié)。研究人員表示，許多患有骨質(zhì)疏松癥的女性實際上遭遇的是類似的問題,，即骨形成與骨重吸收之間的不平衡,。結(jié)果是，雖然形成了足夠的骨,，但是重吸收的速率卻反常地高,，從而無法維持一個健康的骨骼。
研究人員表示,，將來的研究將著重關(guān)注Notch功能的喪失對造骨細胞和破骨細胞間信號通路的干擾,。這也意味著，Notch蛋白和相關(guān)細胞路徑或許可作為藥靶,，以治療某些類型的骨病,。
生物谷推薦原始出處：
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.
