Extracellular signaling molecules to promote fracture healing and bone regeneration.

To date, the delivery of signaling molecules for bone regeneration has focused primarily on factors that directly affect the bone formation pathways (osteoinduction) or that serve to increase the number of bone forming progenitor cells. The first commercialized growth factors approved for bone regeneration, Bone Morphogenetic Protein 2 and 7 (BMP2 and BMP7), are direct inducers of osteoblast differentiation. As well, newer generations of potential therapeutics that target the Wnt signaling pathway are also direct osteoinducers. On the other hand, some signaling molecules may play a role as mitogens and serve to increase the number of bone producing cells or may increase vascularization. This is true for factors such as Platelet Derived Growth Factor (PDGF) or Fibroblast Growth Factor (FGF). Vascular Endothelial Growth Factor (VEGF) likely has a special role. Not only does it induce new blood vessel formation, it also has direct effects on osteoblasts through endothelial cell-based BMP production. In addition to these pathways that classically have targeted bone production, there are also opportunities to target other aspects of the bone healing process such as inflammation, vascularization, and cell ingress to the fracture site. Bone regeneration is highly complex with defined, yet overlapping stages of healing. We will review established and novel extracellular signaling factors associated with various stages of fracture healing that could be targeted to promote enhanced bone regeneration. Importantly, multiple potential cell and tissues could be targeted to enhance healing in addition to focusing solely on osteoinductive therapeutics.