Bone Abstracts

About two decades ago, evidence was generated that canonical Wnt signaling plays an important role in bone accrual mainly based on the identification of mutations in genes from the Wnt pathway resulting in extremely low or high bone mass. Since then, it became clear that genetic variation in a lot of genes from this pathway have an influence on bone mass both in a number of skeletal dysplasias as well as in the general population. This is the case for a number of wnt ligands (wnt1, wnt3, wnt4, wnt5B, wnt16,…), the co-receptor LRP5 and some intracellular partners of this pathway (Axin1 and CTNNB1). Because of its important role in several biological processes, there is a need for strong regulation of the Wnt signaling pathway. This is being done at different levels. Extracellularly, a number of inhibitors are identified. The sFRP’s bind directly to wnt ligands and genetic variance in the sFRP4 gene influences bone mass. The DKK gene family includes 4 inhibitors of the pathway with especially DKK1 being involved in bone homeostasis. Sclerostin encoded by the SOST gene is a bone specific inhibitor secreted from osteocytes. Absence of functional sclerostin results in Van Buchem disease and sclerosteosis, both characterized by extremely high bone mass. Its crucial role in regulating bone homeostasis was corroborated by the evidence that specific missense mutations in the co-receptor LRP5 which disrupt the binding between sclerostin and LRP5 also result in high bone mass. Along the same lines, some missense mutations in LRP4, that seems to act as an anchor for sclerostin in the bone, result in disruption of the binding with sclerostin and subsequently high bone mass. Finally, the R-spondins are transmembraneous activators of canonical Wnt signaling and especially RSPO3 seems to affect bone mass. In conclusion, a lot of evidence has been generated, initially in genetic studies and subsequently corroborated by in vitro functional studies and animal models, to illustrate the essential role of canonical Wnt signaling in bone formation and homeostasis. Therefore, this pathway has been considered an interesting target to identify novel treatments for osteoporosis with very promising results.

Disclosure: The authors declared no competing interests.