Bone mass is inversely proportional to Dkk1 levels in mice
Bone mass is inversely proportional to Dkk1 levels in mice
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DOI：
10.1016/j.bone.2007.05.009
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发表时间：
2007-09-01
期刊：
影响因子：
4.1
通讯作者：
Hauschka, Peter V.
中科院分区：
文献类型：
--
作者：
MacDonald, Bryan T.;Joiner, Danese M.;Hauschka, Peter V.
Wnt/β-连环蛋白信号通路已成为骨发育和骨稳态的关键调节因子。Writ共受体LRP 5中的功能丧失突变导致骨质疏松症，而LRP 5中的“激活”突变导致高骨量。Dickkopf-1（DKK 1）是一种分泌型Wnt抑制剂，在胚胎发育期间结合LRP 5和LRP 6，因此预计DKK 1的减少将导致Wnt活性增加和高骨量表型。Dkk 1（-/-）基因敲除小鼠是胚胎致死的，但是具有表达少量Dkk 1的亚型Dkk 1d（doubleridge）等位基因的小鼠是存活的。在这项研究中，我们通过将Dkk 1（+/-）和Dkk 1（+/d）小鼠杂交产生了一个等位基因系列，产生了以下Dkk 1表达水平降低的基因型：+/+，+/d，+/-和d/-。使用mu CT成像，我们扫描了来自8周龄小鼠（n=60）的解剖的左股骨和颅骨。我们分析了股骨远端代表松质骨，股骨骨干代表皮质软骨内骨。顶骨的一个区域用于分析颅骨的膜内骨。我们发现，Dkk 1突变小鼠的骨小梁体积增加的方式是成反比的Dkk 1表达水平。在雌性和交配小鼠的低Dkk 1表达基因型中，小梁数量和厚度显著较高。在皮质骨中也发现了类似的结果，股骨干皮质厚度和横截面积的增加与Dkk 1表达降低相关。在颅骨测量中没有发现一致的差异。我们的研究结果表明，进行性Dkk 1减少增加骨小梁和皮质骨质量，甚至25%的Dkk 1表达减少可以产生显着增加骨小梁体积分数。因此，DKK 1是体内正常骨稳态的负调节剂。我们的研究表明，DKK 1功能或表达的操纵可能对低骨量疾病的治疗具有治疗意义。(C)2007爱思唯尔公司All rights reserved.
The Wnt/beta-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Writ co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1(-/-) knockout mice are embryonic lethal, but mice with hypomorphic Dkk1d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1(+/-) and Dkk1(+/d) mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/- and d/-. Using mu CT imaging we scanned dissected left femora and calvariae from 8-week-old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and mate mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders. (C) 2007 Elsevier Inc. All rights reserved.