PDF(Pubmed)
Abstract：
Osteoblast Wnt/β-catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low-density lipoprotein receptor-related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β-propeller of LRP5 or LRP6, thereby disassociating these cognate co-receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle-aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z-scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
摘要：
成骨细胞Wnt/β-连环蛋白信号传导调节骨骼发育和健康。当在成骨细胞表面Wnt与低密度脂蛋白受体相关蛋白5（LRP5）或6（LRP6）结合时，骨形成受到刺激，又耦合到卷曲的受体。如果硬骨素和dickkopf1选择性地连接到LRP5或LRP6的第一个β-螺旋桨，则抑制成骨，从而使这些同源共受体与卷曲受体分离。自2002年以来在LRP5中发现的16个杂合突变和自2019年以来在LRP6中发现的3个杂合突变阻止了硬化蛋白或dickkopf1的这种结合，并且是非常罕见的，但很有启发性,常染色体显性疾病称为LRP5和LRP6高骨量（HBM）。在这里，我们在第一个大型受影响的家庭中描述了LRP6HBM。他们的新杂合LRP6错义突变（c.719C>T，p.Thr240Ile）出现在两个中年姐妹和三个儿子中。他们认为自己很健康。他们的宽阔的下巴和圆环在童年时期发展，与LRP6HBM的前两份报告相反，他们成年牙列的外观并不明显。骨骼建模,射线照相定义，支持分类为骨内膜增生。腰椎和全髋关节的骨矿密度（g/cm2）加速增加，分别达到〜8和6的Z值，虽然骨形成的生化标志物是正常的。©2023作者。JBMRPlus由WileyPeriodicalsLLC代表美国骨骼和矿物研究学会出版。
