Abstract
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.
Highlights
In the last decades, plenty of examples have been generated where the identification of causal genes for rare, monogenic diseases resulted in novel insights into the role and functioning of already known pathways
A textbook example of this is Wingless and int-1 (WNT; pronounced “wint”) signaling and its role in bone formation and homeostasis. First indications of this involvement were generated by studying rare monogenic conditions with abnormal bone mass, delivering novel targets for drug development for osteoporosis, a common disorder characterized by decreased bone mass in late life
The name WNT was introduced almost 30 years ago referring to the wingless-type mouse mammary tumor virus integration site which was the first member from this gene family being described [1, 2]
Summary
Plenty of examples have been generated where the identification of causal genes for rare, monogenic diseases resulted in novel insights into the role and functioning of already known pathways. A textbook example of this is Wingless and int-1 (WNT; pronounced “wint”) signaling and its role in bone formation and homeostasis. First indications of this involvement were generated by studying rare monogenic conditions with abnormal bone mass, delivering novel targets for drug development for osteoporosis, a common disorder characterized by decreased bone mass in late life. An antibody against a WNT signaling inhibitor was approved as an anabolic agent for the treatment of osteoporosis
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