LRP4基因突变,编码Wnt信号传导共受体,已发现引起几种等位基因条件。其中,两个的特点是强烈的骨骼受累,即硬化病和塞纳尼-伦茨综合征。在这项工作中,我们评估了LRP4在这些疾病的病理生理学中的作用。首先,我们报道了一个新的LRP4突变,导致谷氨酰胺1170位的精氨酸取代,在一个患有硬化病的病人身上发现的.该突变位于第三β-螺旋桨域的中心腔,这与我们之前描述的另外两个硬化病突变一致。报告分析证明,该突变导致Wnt信号传导的硬化蛋白抑制受损。此外,我们比较了这种新变异与导致Cenani-Lenz综合征的突变的影响,并表明LRP4蛋白的膜运输受损是Cenani-Lenz综合征的可能机制.这与硬化病突变相反,先前显示削弱LRP4和硬化素之间的结合。此外,为了更好地了解LRP4的生物学特性,我们调查了1例LRP4突变导致的硬化病患者血清循环硬化蛋白水平.我们证明硬化蛋白与突变的LRP4蛋白的结合受损导致该患者循环硬化蛋白的急剧增加。通过这项研究,我们提供了第一个证据,表明LRP4是导致骨环境中硬骨素滞留的原因。这些发现引起了人们对确定循环硬化素水平作为其他骨相关参数标记物的实用性的潜在担忧。尽管需要更多的研究来充分了解LRP4促进硬化素作用的机制,很明显,这种蛋白质代表了未来骨质疏松症治疗的有效靶点,也是目前正在研究的抗硬化素治疗的有趣替代方案。
Mutations in the LRP4 gene, coding for a Wnt signaling coreceptor, have been found to cause several allelic conditions. Among these, two are characterized by a strong skeletal involvement, namely
sclerosteosis and Cenani-Lenz syndrome. In this work, we evaluated the role of LRP4 in the pathophysiology of these diseases. First, we report a novel LRP4 mutation, leading to the substitution of arginine at position 1170 in glutamine, identified in a patient with
sclerosteosis. This mutation is located in the central cavity of the third β-propeller domain, which is in line with two other
sclerosteosis mutations we previously described. Reporter assays demonstrate that this mutation leads to impaired sclerostin inhibition of Wnt signaling. Moreover, we compared the effect of this novel variant to mutations causing Cenani-Lenz syndrome and show that impaired membrane trafficking of the LRP4 protein is the likely mechanism underlying Cenani-Lenz syndrome. This is in contrast to
sclerosteosis mutations, previously shown to impair the binding between LRP4 and sclerostin. In addition, to better understand the biology of LRP4, we investigated the circulating sclerostin levels in the serum of a patient suffering from
sclerosteosis owing to a LRP4 mutation. We demonstrate that impaired sclerostin binding to the mutated LRP4 protein leads to dramatic increase in circulating sclerostin in this patient. With this study, we provide the first evidence suggesting that LRP4 is responsible for the retention of sclerostin in the bone environment in humans. These findings raise potential concerns about the utility of determining circulating sclerostin levels as a marker for other bone-related parameters. Although more studies are needed to fully understand the mechanism whereby LRP4 facilitates sclerostin action, it is clear that this protein represents a potent target for future osteoporosis therapies and an interesting alternative for the antisclerostin treatment currently under study.