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Low-density-lipoprotein receptor related protein 5 (LRP5) is a single pass transmembrane receptor that belongs to LDL receptor super-family. One function of LRP5 is to bind to a family of secreted glycoproteins (Wnt ligands) and transduce Wnt signaling. Mutations in LRP5 cause the autosomal recessive Osteoporosis-Pseudoglioma syndrome (OPPG), which is characterized by skeletal fragility due to markedly reduced bone mineral density and by congenital or childhood-onset of blindness. Additional mutations in LRP5 result in autosomal dominant high bone mass (HBM) diseases that are characterized by increased bone mineral density and a reduced incidence of skeletal fracture. This work describes in vitro biochemical studies that delineate the mechanism by which mutations cause HBM (chapter 2), the clinical and molecular features of OPPG (chapter 3), and in vivo studies of Lrp5 knock-out mice to understand the roles of the receptor in osteoblast function and their response to mechanical stress (chapter 4). Since LRP5 protein plays an important role in maintaining healthy bone mineral content, the findings presented in this thesis advanced our understanding of the mechanisms of several rare skeletal diseases, and provided new insights into common skeletal disorders, such as osteoporosis.