Impaired Wnt Signaling as a Cause of Skeletal Disorders

Skeletal development, growth, and remodeling are highly complex processes involving many specific interactions between different cell types, as well as the formation of intact extracellular matrices. Moreover, bone is a highly dynamic tissue undergoing steady remodeling by two fundamentally different cell types, i.e., bone-forming osteoblasts and bone-resorbing osteoclasts. In the last decades, pathogenic variants in a large number of genes have been identified to cause inherited disorders characterized by specific disturbances in the function of distinct skeletal cell types. Whereas several of these skeletal disorders with impaired extracellular matrix production and associated skeletal dysplasia are discussed in other chapters of this book, the focus of the present chapter is related to skeletal disorders caused by pathogenic variants in genes encoding modulators of the Wnt signaling pathway. Importantly, triggered by the genetic analysis of patients with osteosclerotic disorders, i.e., high bone mass due to activation of matrix-producing osteoblasts, these findings have paved the way to develop an efficient osteoanabolic medication. More specifically, Romosozumab, a monoclonal antibody neutralizing the function of Sclerostin was established to increase the activity of the Wnt co-receptor Lrp5, which promotes bone formation by osteoblasts. Besides Sclerostin and Lrp5, there are however other components of the Wnt signaling pathway that play important roles in skeletal biology, as identified by human genetics. This chapter therefore summarizes the current knowledge on impaired Wnt signaling as a cause of skeletal disorders.