OPPG is characterized by severe, early-onset osteoporosis and is also associated with abnormal eye vasculature . In 2001, the underlying genetic mutation for this autosomal
recessive disorder was found to be inactivating mutations in the gene encoding LRP5 . This report was followed shortly by two manuscripts showing that some patients with an inherited predisposition to high bone mass carry a point mutation in LRP5 (G171V) that is causally associated with the increased bone mass  and . Subsequent generation of mice carrying germline inactivating mutations in Lrp5 further confirmed the importance of this gene by accurately modeling phenotypes observed in OPPG syndrome ,  and . In addition, a strain of mice expressing the G171V version of Lrp5 specifically in osteoblasts developed high bone mass, further confirming role of Lrp5 in skeletal homeostasis . While the mechanisms underlying the effect of LRP5 mutations on bone mass are GSK2118436 concentration still being
debated in the literature, an important advance came from studies on two other disorders associated with increased bone mass: sclerosteosis and van Buchem disease . Both disorders are caused by loss of expression of the gene SOST, which encodes the protein sclerostin  and . In sclerosteosis, this loss is due to inactivating mutations in the coding region, while the underlying defect in van Buchem disease is a 52-kilobase deletion in a putative regulatory element necessary for expression of SOST . Subsequent selleck inhibitor studies found that SOST, which is specifically secreted from osteocytes ,  and  and some types of chondrocytes ,  and ,
is normally bound to the LRP5 protein to inhibit its signaling ,  and . In patients with the high bone mass associated mutation in LRP5, the ability of SOST to bind and 2-hydroxyphytanoyl-CoA lyase down-regulate LRP5 function is lost, leading to increased bone growth , ,  and . Other proteins such as dickkopf 1 (DKK1) and mesoderm development (MESD) also bind to wild-type LRP5 ,  and , but not to mutant forms of LRP5 linked to high bone mass . This evidence, combined with several mouse models in which LRP5 (and the related LRP6 protein) function is specifically altered within the osteoblast and osteocyte lineage ,  and , has led to a model proposing that Lrp5 and Lrp6 function within osteoblasts to regulate osteoblast function. It should be noted that another model has been proposed, in which Lrp5 is involved in the regulation of serotonin secretion from the enterrochromaffin cells of the intestine . Alterations in serum serotonin then lead to changes in osteoblast function. The relative contributions of these two models are still being assessed. For a more thorough discussion of the current status of therapies targeting serotonin, we refer readers to a recent review on this topic . Osteocytes express several known inhibitors of the Wnt/β-catenin pathway.