Wnt signaling during fracture repair

Abstract

Bone is one of the few tissues in the body with the capacity to regenerate and repair itself. Fractures usually are completely repaired in a relatively short time, but in a small percentage of cases, healing never occurs and nonunion is the result. Fracture repair and bone regeneration require the localized reactivation of signaling cascades that are crucial for skeletal development. The Wnt/beta-catenin signaling pathway is one such developmental pathway whose role in bone formation and regeneration recently has been appreciated. During the past decade, much has been learned about how Wnt pathways regulate bone mass. Small molecules and biologics aimed at this pathway are now being tested as potential new anabolic agents. This article reviews recent data demonstrating that Wnt pathways are active during fracture repair and that increasing the activities of Wnt pathway components accelerates bone regeneration.

Figure 1. Wnts initiate multiple signaling pathways

The “canonical pathway” (center) is stimulated when Wnts bind to Fzd receptors and Lrp5/6 co-receptors. A cytoplasmic complex composed of GSK3β, Axin, and APC is inhibited, allowing cytoplasmic levels of β-catenin levels to rise. Some β-catenin translocates to the nucleus where it associates with Tcf/Lef transcription factors to regulate gene expression. During non-canonical Wnt signaling (left), Wnts bind to a Fzd receptor, Ryk or Ror2, and activate downstream signaling events that do not involve GSK3β or β-catenin. Wnt signaling pathways are inhibited by several mechanisms (right). Secreted frizzled-related proteins (Sfrps) antagonize canonical Wnt signaling by binding the ligands and preventing their association with Fzd receptors. Dkk1 suppresses Wnt signaling by forming a ternary complex with Lrp5/6 and Krm1/2. Sclerostin (Scl) also binds to Lrp5/6, but not Krm1/2, to antagonize canonical Wnt signaling. In the absence of Wnt/Lrp signaling, GSK3β phosphorylates (asterisks) β-catenin, which marks it for ubiquitination and proteosomal degradation.