Recent advancements in genetic research have uncovered new forms of monogenic osteoporosis, expanding our understanding of the molecular pathways regulating bone health. Despite active research, knowledge on the pathomechanisms, disease-specific biomarkers, and optimal treatment in these disorders is still limited. Mutations in WNT1, encoding a WNT/β-catenin pathway ligand WNT1, and PLS3, encoding X chromosomally inherited plastin 3 (PLS3), both result in early-onset osteoporosis with prevalent fractures and disrupted bone metabolism. However, despite marked skeletal pathology, conventional bone markers are usually normal in both diseases. Our study aimed to identify novel bone markers in PLS3 and WNT1 osteoporosis that could offer diagnostic potential and shed light on the mechanisms behind these skeletal pathologies. We measured several parameters of bone metabolism, including serum dickkopf-1 (DKK1), sclerostin, and intact and C-terminal fibroblast growth factor 23 (FGF23) concentrations in 17 WNT1 and 14 PLS3 mutation-positive subjects. Findings were compared with 34 healthy mutation-negative subjects from the same families. Results confirmed normal concentrations of conventional metabolic bone markers in both groups. DKK1 concentrations were significantly elevated in PLS3 mutation-positive subjects compared with WNT1 mutation-positive subjects (p < .001) or the mutation-negative subjects (p = .002). Similar differences were not seen in WNT1 subjects. Sclerostin concentrations did not differ between any groups. Both intact and C-terminal FGF23 were significantly elevated in WNT1 mutation-positive subjects (p = .039 and p = .027, respectively) and normal in PLS3 subjects. Our results indicate a link between PLS3 and DKK1 and WNT1 and FGF23 in bone metabolism. The normal sclerostin and DKK1 levels in patients with impaired WNT signaling suggest another parallel regulatory mechanism. These findings provide novel information on the molecular networks in bone. Extended studies are needed to investigate whether these biomarkers offer diagnostic value or potential as treatment targets in osteoporosis. © 2020 American Society for Bone and Mineral Research.

中文翻译：

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WNT1 和 PLS3 骨质疏松症中的生物标志物：DKK1 和 FGF23 的浓度改变。

基因研究的最新进展揭示了新形式的单基因骨质疏松症，扩大了我们对调节骨骼健康的分子途径的理解。尽管进行了积极的研究，但关于这些疾病的病理机制、疾病特异性生物标志物和最佳治疗的知识仍然有限。编码 WNT/β-catenin 通路配体 WNT1 的 WNT1 和编码 X 染色体遗传的 plastin 3 (PLS3) 的 PLS3 的突变都导致早发性骨质疏松症，伴有普遍的骨折和破坏的骨代谢。然而，尽管有明显的骨骼病理学，传统的骨标志物在这两种疾病中通常都是正常的。我们的研究旨在确定 PLS3 和 WNT1 骨质疏松症中的新骨标志物，这些标志物可以提供诊断潜力并阐明这些骨骼病理学背后的机制。我们测量了 17 名 WNT1 和 14 名 PLS3 突变阳性受试者的几个骨代谢参数，包括血清 dickkopf-1 (DKK1)、硬化蛋白、完整和 C 末端成纤维细胞生长因子 23 (FGF23) 浓度。将研究结果与来自同一家庭的 34 名健康突变阴性受试者进行了比较。结果证实两组的常规代谢骨标志物浓度正常。与 WNT1 突变阳性受试者 (p < .001) 或突变阴性受试者 (p = .002) 相比，PLS3 突变阳性受试者的 DKK1 浓度显着升高。在 WNT1 受试者中没有看到类似的差异。任何组之间的硬化蛋白浓度没有差异。在 WNT1 突变阳性受试者中，完整和 C 末端 FGF23 均显着升高（p = .039 和 p = .027，分别）和正常的PLS3科目。我们的结果表明 PLS3 和 DKK1 以及 WNT1 和 FGF23 在骨代谢中的联系。WNT 信号受损患者的正常硬化蛋白和 DKK1 水平表明了另一种平行的调节机制。这些发现为骨骼中的分子网络提供了新的信息。需要进一步的研究来调查这些生物标志物是否具有诊断价值或作为骨质疏松症治疗靶点的潜力。© 2020 美国骨与矿物研究学会。需要进一步的研究来调查这些生物标志物是否具有诊断价值或作为骨质疏松症治疗靶点的潜力。© 2020 美国骨与矿物研究学会。需要进一步的研究来调查这些生物标志物是否具有诊断价值或作为骨质疏松症治疗靶点的潜力。© 2020 美国骨与矿物研究学会。