Where Wnts Went: The Exploding Field of Lrp5 and Lrp6 Signaling in Bone

Wnt signaling has emerged as a central regulator of skeletal modeling and remodeling. Loss- or gain-of-function mutations in two Writ co-receptors, Lrp5 and (more recently) Lrp6, have drawn attention to the importance of the Writ pathway in bone biology. This review summarizes our current understanding of how the Wilt pathway operates on bone and the implications this has for skeletal physiology and drug discovery. Over the past 9 yr, rapid advances have been made in our understanding of the cellular targets for Writ signaling and of the important regulatory molecules in this metabolic pathway. Both canonical and noncanonical signaling pathways seem to be important for mediating the effects of Writ in bone. A rapidly expanding catalog of genetically engineered mice has been used to establish the importance of downstream effector molecules (such as beta-catenin) in the Writ pathway, as well as the critical role of endogenous inhibitors of Writ signaling (such as Dkk1 and sclerostin) in bone metabolism. Indeed, regulation of sclerostin in osteocytes is emerging as an Important final pathway for regulating bone anabolism in response to diverse trophic stimuli, from mechnotransduction to the anabolic actions of PTH. From the outset, it had been assumed that the effects of Writ signaling in bone were caused by direct actions in osteoblast precursors, osteoblasts, and osteocytes. However, starting recent findings have challenged this view and suggest that a key target, at least in mice, is the duodenal enterochromaffin cell. There, Writ signaling transduced by Lrp5 regulates serotonin synthesis, which acts in an endocrine fashion to regulate bone cell metabolism. It will take time to reconcile this new information with the considerable body of information we already have regarding the actions of Writ in bone. The Writ pathway has rapidly emerged as a therapeutic target for drug discovery. Neutralizing antibodies and small-molecule inhibitors of endogenous Wnt inhibitors have shown early promise as bone anabolic agents. However, given the central role of the Writ pathway in regulating growth and development in extraskeletal tissues, as well as our still rudimentary understanding of how this signaling cascade actually affects bone metabolism, considerable work will be needed to ensure the safety of these new therapies.