Wnt Proteins Promote Bone Regeneration

A liposome-encased ligand for the Wnt signaling pathway can accelerate bone regeneration after injury. Some of the best medicines act as facilitators. They tweak the body’s systems so that its own homeostatic mechanisms can more easily return things to normal. One potentially tweakable process is the Wnt signaling pathway, a soluble ligand-receptor system that controls transcription of β-catenin and other genes. This pathway is used over and over again for specification of the body axis and morphogenesis during development and goes awry in cancer. Minear and colleagues noted that Wnt signaling participates in regrowth and healing of broken bones and found a way to augment its action. Their treatment accelerates natural recovery from bone injury. The authors used genetically altered mice to show that Wnt signaling is increased in regions in which bone is healing, which suggests that it participates in the bone regeneration process. By interfering with the action of a Wnt signaling inhibitor, they potentiated this pathway even more, which resulted in more rapid healing of small holes that they made in the tibial bone of the mice. To begin to translate these results to patients, the authors then increased Wnt signaling in these mice with an approach that, unlike genetic manipulation, could be replicated in the clinic. Getting around the fact that Wnt ligands are insoluble in aqueous solution by using a liposome package, the authors applied Wnt-filled liposomes to healing bone and again showed faster healing. The basis of this effect was both the simulation of skeletal progenitor cell proliferation and the promotion of differentiation of these progenitors into osteoblasts, the cellular builder of bone. Wnt packaged in lipid membrane vesicles could have advantages over other treatments that can facilitate bone healing, specifically bone morphogenetic protein, because of the advantageous type of bone that is created. And the fact that the Wnt pathway controls numerous fundamental processes may mean that Wnt-containing vesicles could prove useful in tweaking other systems to help the body more rapidly achieve healing and homeostasis. The Wnt signaling pathway plays a central role in bone development and homeostasis. In most cases, Wnt ligands promote bone growth, which has led to speculation that Wnt factors could be used to stimulate bone healing. We gained insights into the mechanism by which Wnt signaling regulates adult bone repair through the use of the mouse strain Axin2LacZ/LacZ in which the cellular response to Wnt is increased. We found that bone healing after injury is accelerated in Axin2LacZ/LacZ mice, a consequence of more robust proliferation and earlier differentiation of skeletal stem and progenitor cells. In parallel, we devised a biochemical strategy to increase the duration and strength of Wnt signaling at the sites of skeletal injury. Purified Wnt3a was packaged in liposomal vesicles and delivered to skeletal defects, where it stimulated the proliferation of skeletal progenitor cells and accelerated their differentiation into osteoblasts, cells responsible for bone growth. The end result was faster bone regeneration. Because Wnt signaling is conserved in mammalian tissue repair, this protein-based approach may have widespread applications in regenerative medicine.