Center of Medical Genetics, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium.
Front Endocrinol (Lausanne). 2020 Apr 9;11:165. doi: 10.3389/fendo.2020.00165. eCollection 2020.
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.
骨骼发育不良是一组遗传性疾病，影响骨骼和软骨的生长。多年来，许多疾病的分子缺陷已经被确定。这些鉴定为调节骨骼和软骨生长和平衡的机制提供了新的见解。在骨骼发育和骨稳态过程中非常重要的途径之一是无翅型和 int-1（WNT）信号通路。到目前为止，已经描述了三种不同的 WNT 信号通路，它们都通过 WNT 配体与 Frizzled（FZD）受体的结合而被激活。在这篇综述中，我们讨论了最新骨骼疾病分类学中包含的骨骼疾病，这些疾病是由涉及 WNT 信号通路的遗传缺陷引起的。由 WNT 信号基因缺陷引起的骨骼疾病的数量以及与这些疾病相关的临床表型表明 WNT 信号通路在骨骼发育以及生命后期维持骨量方面的重要性。通过鉴定这些单基因疾病的基因所获得的知识被用于确定新的治疗靶点。例如，与骨量改变相关的疾病的基因都涉及经典的 WNT 信号通路。因此，靶向该途径是增加骨质疏松症患者骨量的主要策略之一。除了增加对调节骨骼发育和骨稳态的途径的了解外，对罕见骨骼发育不良的了解也可用于预测这些新型药物靶点的可能不良反应。因此，本综述概述了与 WNT 信号通路相关的不同骨骼疾病的骨骼和骨骼外表型。
