Recently, the first clinical reports on bone regeneration by two recombinant human bone morphogenetic proteins (rhBMPs), BMP-2 and BMP-7 (also named osteogenic protein-1, OP-1) have been published (1-4) . Although both BMPs were able to support bone regeneration, a significant variation in individual response was observed with both proteins. Animal studies and laboratory experiments reveal a number of conditions that influence the osteoinductivity of BMP, such as BMP concentration, carrier properties and influence of local and systemic growth factors and hormones. In this paper, these studies and the clinical reports are reviewed, and the conditions that modulate the BMP-dependent osteoinduction are discussed. The information may provide clues as to how the performance of recombinant human BMP as bone-graft substitute in humans can be improved.
European Journal of Endocrinology 142 9-21
BMP and demineralized bone matrixThe history of bone morphogenetic proteins (BMPs) began with the observation that demineralized bone matrix (DBM) is able to induce ectopic bone formation in subcutaneous and intramuscular pockets in rodents (5, 6). This bone induction process has been studied extensively (7-13). Histological and biochemical analyses showed that cartilage appears 5-10 days after implantation of active DBM (8). This cartilage mineralizes by day 7-14 and is subsequently replaced by bone (7-9). After 21 days, haematopoietic bone marrow formation can be observed (12). These cellular events observed after DBM implantation mimic embryonic bone development and normal fracture repair (11). As DBM-related bone formation was observed to occur at ectopic sites, it was assumed that pluripotent mesenchymal cells are attracted to the site of implantation. Isolation of the bone-inducing substance revealed that certain proteins were responsible, which were termed bone morphogenetic proteins (BMPs) or osteogenetic proteins (OPs).The use of DBM in treating bone defects has proven beneficial for bone regeneration both in animals and in humans (14-17). DBM has become widely accepted as a bone-graft substitute in clinical practice (18-22), but its bone inductive capacity has been questioned (23, 24). In several studies, including our own, histology revealed that new bone was generated by osteoconduction rather than osteoinduction (25-27) -that is, bone regeneration occurred by growth of existing host bone on the DBM granules, which acted as a scaffold, rather than by de novo differentiation of bone, independent of pre-existing bone. Lack of inductive properties of DBM may be related to the procedures of production of commercially available DBM, as preservation of osteoinductive activity can be affected by the processing (28-30) or sterilization procedures (31). It is also possible that DBM of human origin, which is preferred for use in clinical practice, is less osteoinductive than DBM derived from animals, which is commonly used in animal studies. Several studies show that DBM from long-lived species such as baboon and human...