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Dibotermin alfa is a recombinant human bone morphogenetic protein-2 (rhBMP-2) derived from a recombinant Chinese Hamster Ovary (CHO) cell line . It is implanted in patients undergoing bone surgeries or those with fractures. BMPs are subfamily of the transforming growth factor-β (TGF-β) superfamily that have different actions on the bone matrix . BMP-2 is a potent osteoinductive protein that plays a critical role in the differentiation of osteoprogenitor cells into osteoblasts, thus promoting bone and cartilage formation . Through enhancing osteogenesis at the site of implantation, dibotermin alfa accelerates the healing of open tibial shaft fractures and reduces the need for secondary intervention . In a prospective clinical study of patients with an open tibial fracture, administration of dibotermin alfa resulted in faster fracture- or wound-healing, significantly fewer secondary invasive interventions, and reduced infection rate post-operation . Dibotermin alfa was approved by the EMA in 2002 as Inductos for implantation matrix. In 2004, it was approved by the FDA and is marketed as Infuse. In Infuse, rhBMP is a disulfide-linked dimeric protein molecule with two major subunit species of 114 and 131 amino acids. Each subunit is glycosylated with high-mannose-type glycans .
Dibotermin alfa is a recombinant human bone morphogenetic protein-2 (rhBMP-2) derived from a recombinant Chinese Hamster Ovary (CHO) cell line . It is implanted in patients undergoing bone surgeries or those with fractures. BMPs are subfamily of the transforming growth factor-β (TGF-β) superfamily that have different actions on the bone matrix . BMP-2 is a potent osteoinductive protein that plays a critical role in the differentiation of osteoprogenitor cells into osteoblasts, thus promoting bone and cartilage formation . Through enhancing osteogenesis at the site of implantation, dibotermin alfa accelerates the healing of open tibial shaft fractures and reduces the need for secondary intervention . In a prospective clinical study of patients with an open tibial fracture, administration of dibotermin alfa resulted in faster fracture- or wound-healing, significantly fewer secondary invasive interventions, and reduced infection rate post-operation . Dibotermin alfa was approved by the EMA in 2002 as Inductos for implantation matrix. In 2004, it was approved by the FDA and is marketed as Infuse. In Infuse, rhBMP is a disulfide-linked dimeric protein molecule with two major subunit species of 114 and 131 amino acids. Each subunit is glycosylated with high-mannose-type glycans .
In the same pathway shared by endogenous BMPs, recombinant human BMP-2 (rhBMP-2) binds and initiates intracellular signal cascade through an oligomeric transmembrane receptor complex formed by type I and II serine/threonine kinase receptor proteins . These BMP receptors are expressed on the surface of mesenchymal cells and upon binding of BMP-2 to the BMP receptor type II, type II receptor phosphorylates and activates type I receptor. Type I receptor may also undergo autophosphorylation. Activated BMP type I receptor then phosphorylates intracellular effector proteins, the receptor-regulated Smads (R-Smads) . Smad1, Smad 5 and Smad 8 associate with the Co-Smad, Smad4 and once activated via complex formation, they translocate to the nucleus where they associate with other transcription factors and bind promoters of target genes to control their expression . This ultimately results in bone formation at the site of implantation. Dibotermin alfa causes mesenchymal cells to differentiate into cartilage- and bone-forming cells. Implantation of dibotermin alfa in trabecular bone results in transient resorption of the bone surrounding the implant, followed by replacement of degraded matrix by newly differentiated cells . In human bone cells isolated from adult mandibulae, recombinant human BMP-2 (rhBMP-2) was shown to stimulate the activity of early biomarkers of osteoblast differentiation, including alkaline phosphatase and parathyroid hormone (PTH)-dependent 3', 5'-cyclic adenosine monophosphate accumulation . At concentrations of 500 ng/mL, rhBMP-2 also enhanced the mRNA expression level of PTH/PTH related-peptide receptor in human bone cells . There was evidence that rhBMP-2 inhibits 1,25-dihydroxyvitamin D3-induced osteocalcin synthesis at both the mRNA and protein level. rhBMP-2 also significantly suppressed MMP-1 production and MMP-1 mRNA expression at concentrations exceeding 500 ng/mL .
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