Bone is a tissue that has the capacity to self-repair. However, in some circumstances such as big or complex fractures, or teeth missing, bone is not able to regenerate by itself. In these situations, biomaterials are being used to regenerate or substitute bone, although most of them do not induce proper bone regeneration. One strategy is the use of molecules secreted by cells, such as growth factors, that are immobilized onto the biomaterials in order to mimic the natural bone healing process. In this regard, Bone Morphogenetic Protein-2 (BMP-2) is a growth factor secreted by cells with potent bone regeneration capacities. BMP-2 binds to two different cell surface receptors (type I and type II receptors) activating a downstream signaling cascade that ends with the activation of genes related to bone regeneration. Although its use in biomaterials has been shown promising results, the main problem is that BMP-2 is rapidly degraded upon implantation. Then, huge amounts of BMP-2 have to be implanted, which has been related to side effects such as inflammation or cancer.
Therefore, alternatives to BMP-2 are important for the society because they might be used to reduce or shorten the time recovery of patients that require a biomaterial implantation after bone fracture.
The overall objective of ENGAGE project is to computationally design a synthetic protein that will substitute BMP-2 and stimulate the same activity but with higher stability. Then, less amounts of the designed protein will be required for implantation, which is expected to reduce the undesired side effects associated to BMP-2. To this end, proteins with the ability to bind type I receptors and proteins with the ability to bind type II receptors were designed during ENGAGE and were fused to obtain a single protein with the capacity to induce the BMP-2 downstream signaling cascade.
The execution of ENGAGE project has demonstrated that it is possible to computationally design proteins that bind to the BMP-2 receptors with higher affinity than the natural BMP-2. These designs will have the potential to substitute the use of BMP-2 potentially producing less side effects. In addition, the individual designs for each single receptor will have the potential to be used as antagonists in those pathological situations where these receptors are overexpressed.
