Modulating Integrin and Growth Factor Signaling With Peptides: Strategies to Synergistically Enhance Bone Tissue Regeneration

Providing biomaterials with cell-instructive cues represents a major goal in tissue engineering to tailor cell-material interactions and guide tissue regeneration. For bone tissue regeneration, this has been classically addressed by integrating integrin-binding proteins and peptides on different substrates, aiming at mimicking the bone extracellular matrix. However, it has become evident that integrin signaling alone is not sufficient to fully recreate the cellular microenvironment required to effectively drive bone healing, and that growth factors (GFs), such as bone morphogenetic proteins (BMPs), are essential for bone development and growth. Indeed, recent research has demonstrated that integrins engage in synergistic signaling with GF receptors (GFRs). For instance, it is now well established that the osteogenic activity of BMPs can be regulated, and often enhanced, by integrins. These findings have thus encouraged the study of novel multifunctional systems that combine integrin-binding ligands with osteoinductive cues to exploit integrin-GF crosstalk and regenerate bone. This review aims to provide a comprehensive overview of the different mechanisms of signaling between integrins and GFRs, and the existing strategies to harness synergistic effects. A particular focus is put on the recent developments using the well-known integrin-binding RGD peptide and its co-presentation with BMP-derived peptides.