Folkhälsan Institute of Genetics, University of Helsinki, Helsinki, Finland.
Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
J Bone Miner Res. 2020 Oct;35(10):1962-1973. doi: 10.1002/jbmr.4097. Epub 2020 Jul 2.
Plastin 3 (PLS3), encoded by PLS3, is a newly recognized regulator of bone metabolism, and mutations in the encoding gene result in severe childhood-onset osteoporosis. Because it is an X chromosomal gene, PLS3 mutation-positive males are typically more severely affected whereas females portray normal to increased skeletal fragility. Despite the severe skeletal pathology, conventional metabolic bone markers tend to be normal and are thus insufficient for diagnosing or monitoring patients. Our study aimed to explore serum microRNA (miRNA) concentrations in subjects with defective PLS3 function to identify novel markers that could differentiate subjects according to mutation status and give insight into the molecular mechanisms by which PLS3 regulates skeletal health. We analyzed fasting serum samples for a custom-designed panel comprising 192 miRNAs in 15 mutation-positive (five males, age range 8-76 years, median 41 years) and 14 mutation-negative (six males, age range 8-69 years, median 40 years) subjects from four Finnish families with different PLS3 mutations. We identified a unique miRNA expression profile in the mutation-positive subjects with seven significantly upregulated or downregulated miRNAs (miR-93-3p, miR-532-3p, miR-133a-3p, miR-301b-3p, miR-181c-5p, miR-203a-3p, and miR-590-3p; p values, range .004-.044). Surprisingly, gender subgroup analysis revealed the difference to be even more distinct in female mutation-positive subjects (congruent p values, range .007-.086) than in males (p values, range .127-.843) in comparison to corresponding mutation-negative subjects. Although the seven identified miRNAs have all been linked to bone metabolism and two of them (miR-181c-5p and miR-203a-3p) have bioinformatically predicted targets in the PLS3 3' untranslated region (3'-UTR), none have previously been reported to associate with PLS3. Our results indicate that PLS3 mutations are reflected in altered serum miRNA levels and suggest there is crosstalk between PLS3 and these miRNAs in bone metabolism. These provide new understanding of the pathomechanisms by which mutations in PLS3 lead to skeletal disease and may provide novel avenues for exploring miRNAs as biomarkers in PLS3 osteoporosis or as target molecules in future therapeutic applications. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
PLS3（编码基因 PLS3）是一种新发现的骨骼代谢调控因子，其编码基因突变会导致严重的儿童期起病骨质疏松症。由于 PLS3 是一个 X 染色体基因，因此 PLS3 突变阳性的男性通常受到的影响更为严重，而女性则表现为骨骼脆弱程度正常或增加。尽管骨骼病理严重，但常规代谢性骨标志物往往正常，因此不足以用于诊断或监测患者。我们的研究旨在探讨 PLS3 功能缺陷患者的血清 microRNA（miRNA）浓度，以确定新的标志物，根据突变状态对患者进行区分，并深入了解 PLS3 调节骨骼健康的分子机制。我们分析了来自四个芬兰 PLS3 突变家族的 15 名突变阳性（5 名男性，年龄 8-76 岁，中位数 41 岁）和 14 名突变阴性（6 名男性，年龄 8-69 岁，中位数 40 岁）受试者的空腹血清样本，该样本使用包含 192 个 miRNA 的定制面板进行分析。我们在突变阳性受试者中发现了一个独特的 miRNA 表达谱，其中有 7 个 miRNA 显著上调或下调（miR-93-3p、miR-532-3p、miR-133a-3p、miR-301b-3p、miR-181c-5p、miR-203a-3p 和 miR-590-3p；p 值范围为.004-.044）。令人惊讶的是，性别亚组分析显示，与相应的突变阴性受试者相比，女性突变阳性受试者的差异更为明显（一致的 p 值范围为.007-.086），而男性的差异则不太明显（p 值范围为.127-.843）。尽管这 7 个已鉴定的 miRNA 均与骨代谢有关，其中两个（miR-181c-5p 和 miR-203a-3p）在 PLS3 的 3'非翻译区（3'-UTR）中有生物信息学预测的靶标，但以前都没有报道过与 PLS3 有关。我们的结果表明，PLS3 突变反映在血清 miRNA 水平的改变中，并提示 PLS3 和这些 miRNA 之间在骨代谢中存在串扰。这些为 PLS3 突变导致骨骼疾病的发病机制提供了新的认识，并可能为探索 PLS3 骨质疏松症中的 miRNA 作为生物标志物或未来治疗应用中的靶分子提供新的途径。
