Regulation of Angiogenesis and Bone Regeneration with Natural and Synthetic Small Molecules

Regeneration of bone requires the coordinated processes of angiogenesis and osteogenesis. These repair mechanisms are closely linked through both direct cell-cell contact and indirect paracrine signaling among osteoblasts, endothelial cells, and other cell types. The vasculature provides a source of nutrients, oxygen, metabolic substrates, and access for circulating cells that help to support new bone formation. The complexity of the endogenous signaling axis that promotes angiogenesis provides numerous opportunities for therapeutic intervention ranging from progenitor cell mobilization to endothelial proliferation and sprouting. Small molecules are particularly appealing for regenerative medicine applications because many exhibit extended in vivo stability, low cost, and scalable production. Innovative techniques for developing small molecules such as high throughput functional assays and broad-spectrum database analysis techniques have led to the development of new compounds and the identification of novel applications of existing drugs. In addition, rapid advances in biomaterials design and synthesis provide platforms to deliver therapeutic small molecules to sites of bone injury. This review presents an overview of current strategies for harnessing endogenous healing mechanisms using small molecules by targeting angiogenesis, osteogenesis, or both.