Bone Morphogenetic Proteins in the Treatment of Non-unions and Bone Defects: Historical Perspective and Current Knowledge

Bone morphogenetic proteins (BMPs) are a family of bone matrix polypeptides which have been isolated from a variety of mammalian species, including man. BMPs initiate chondroblastic differentiation in pluripotent mesenchymal progenitor cells, followed by the synthesis of new bone by enchondral ossification. BMPs have demonstrated the ability to induce healing of osteoperiosteal defects in several animal models, and now in human studies, supporting a role in the reconstruction of bone defects. BMPs are responsible for the osteoinductive capacity of demineralized bone matrix (DBM) implants, which have also been demonstrated to be helpful in healing defects. Recent reports on the use of both purified, naturally occurring, and recombinant human bone morphogenetic proteins in the treatment of non-unions and bone defects have shown promising results. The use of bone morphogenetic protein implants to augment or replace autogenous and allogenous bone grafts will reduce morbidity and circumvent the risk of disease transmission associated with bone transplantation. Segmental bone loss and non-union, whether after reconstructive surgery, lesion excision, or fracture, can present complex problems. An important part of the therapeutic approach to bone defects is the implantation of materials that support new bone formation. Such implants may hasten healing by three mechanisms: osteoconduction, osteogenesis, and osteoinduction. In osteoconduction, implanted material serves as an inert scaffold for the ingrowth of host bone. This includes the differentiation and maturation within the implant of host osteoprogenitor cells, with ingrowth of vascular elements. Ideally, “creeping substitution” then replaces the implant with new bone to form a functional skeletal element [35,51,52]. Osteogenesis is the synthesis of new bone by surviving pre-osteoblasts and osteoblasts within a bone autograft. These cells proliferate and mature into centers of new bone formation. Osteoinduction is the formation of new bone by the active recruitment of host pluripotent cells that differentiate into chondroblasts and osteoblasts [35,51– 53]. The ideal artificial implant would be both osteoinductive and osteoconductive; it would cause new bone to form, then support its replacement of the bone defect. It is now well accepted that osteoinduction is controlled, at least in part, by bone matrix proteins often collectively referred to as bone morphogenetic proteins (BMPs). These proteins are low-molecular weight polypeptides that have been isolated from the bones of a variety of mammalian species, including mouse, rat, bovine, monkey, and man [11,20,36–41,46,48,55]. They are also produced by clonal osteogenic sarcoma cell lines [46,48]. In recent years, bone morphogenetic proteins have been recognized as a potentially powerful clinical tool. Research efforts have been devoted to elucidating their properties and exploring ways in which they may be used to augment or replace bone grafts.