A Single Percutaneous Injection of Recombinant Human Bone Morphogenetic Protein-2 Accelerates Fracture Repair

Einhorn, Thomas A.; Majeska, Robert J.; Mohaideen, Ahamed; Kagel, Eric M.; Bouxsein, Mary L.; Turek, Thomas J.; Wozney, John M.

doi:10.2106/00004623-200308000-00002

Cited by 178 publications

(100 citation statements)

References 27 publications

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“…BMP-2 and BMP-7 have further been demonstrated to enhance bone healing in vivo in animals and humans in settings such as spinal fusion, fracture repair and distraction osteogenesis [23][24][25]. Although there appears to be some benefit from the use of BMPs clinically there continues to be uncertainty about the BMP potential since animal and in vitro models have demonstrated much more potent responses than results observed in cultured human cells or in clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells

Edgar

Chakravarthy

Barnes

et al. 2007

Bone

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The expression patterns of (bone morphogenetic proteins) BMPs during fracture repair and pre-natal bone development suggests that these processes are regulated through the coordinated actions of multiple BMPs. Murine bone marrow stromal cells (MSCs) in culture provide a well recognized ex vivo system of mesenchymal stem cell differentiation in which the effects of BMPs can be examined. Studies were performed to determine if MSC differentiation is dependent on the endogenous expression of multiple BMPs and to characterize their interactions. MSCs were harvested from the bone marrow of tibiae and femora of 8 to 10 week old male C57/B6 mice and prepared by standard methods. Osteogenic differentiation was assessed by histological assays, alkaline phosphatase enzyme activity and assays for the expression of multiple mRNAs for BMPs and osteogenic development. The role of autogenously expressed BMPs in controlling the osteogenic differentiation of marrow stromal cells in vitro was assessed in both gain-of-function and loss-of-function experiments. Gain of function experiments were carried out in the presence of exogenously added BMP-2 or 7 and loss of function experiments were carried out by BMP antagonism with noggin and BMP-2 antibody blockade. Osteogenic differentiation was concurrent with and proportional to increases in the expression of BMPs 2, 3, 4, 5, 6, and 8A. BMP antagonism with either noggin or BMP-2 antibody blockade inhibited osteogenic differentiation by 50% to 80% respectively and reduced the expression of endogenous levels of BMPs 2, 3, 5, and 8A. In contrast, antagonism induced the expression of BMP-4 and 6. The addition of rhBMP-2 or 7 enhanced osteogenic differentiation and produced a reciprocal expression profile in the endogenous BMPs expression as compared to BMP antagonism. BMP antagonism could be rescued through the competitive addition of rhBMP-2. These studies demonstrated that osteogenic differentiation was regulated by a complex network of multiple BMPs that showed selective increased and decreased expression during differentiation. They further demonstrated that BMP-2 was a central regulator in this network.

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Section: Discussionmentioning

confidence: 99%

Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells

Edgar

Chakravarthy

Barnes

et al. 2007

Bone

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“…Clinical and animal experiments have shown that local application of growth factors may accelerate this restoration of vascularization/perfusion and lead to improvement of wound and fracture healing (Mustoe et al 1987, Sprugel et al 1987, Rifkin andMoscatelli 1989, Klingbeil et al 1991, Yasko et al 1992, Albertson et al 1993, Lind et al 1993, Kawaguchi et al 1994, Nash et al 1994, Nielsen et al 1994, Steenfos et al 1994, Heckman et al 1995, Nagai et al 1995, Richard et al 1995, Okumura et al 1996, Wang and Aspenberg 1996, Beer et al 1997, Davidson et al 1997, Leunig et al 1997, Bostrom and Camacho 1998, Kato et al 1998, McGee et al 1998, Wieman et al 1998, Corral et al 1999, Radomsky et al 1999, Bouxein et al 2001, Govender et al 2002, Luppen et al 2002, Einhorn et al 2003, Hom and Manivel 2003.…”

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Local application of basic fibroblast growth factor increases the risk of local infection after trauma: An in-vitro and in-vivo study in rats

et al. 2007

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Introduction Local application of growth factors to stimulate wound and fracture healing is attracting increasing interest. We studied the effect of local application of a potent angiogenic growth factor, basic fibroblast growth factor (bFGF), on resistance to local infection after soft tissue trauma.Methods For in-vitro and in-vivo experiments, we used recombinant human bFGF. The in-vitro investigations were performed by isolation of human leukocyte fractions, cytokine analysis, phagocytosis assay, flow cytometry, and LDH assay. For the in-vivo investigation, a paired comparison of infection rates was carried out on Sprague-Dawley rats after standardized, closed soft tissue trauma and local, percutaneous bacterial inoculation of different concentrations of Staphylococcus aureus (2 × 10 4 to 2 × 10 7 colony-forming units (cfu)). The lower leg was treated with 1, 10 or 100 ng bFGF (16 animals for each concentration) and without bFGF (16 animals).Results Cytotoxic reactions due to the concentrations of bFGF used could be excluded in the in-vitro tests since incubations of isolated peripheral blood mononuclear cells (PBMCs) with increasing concentrations of bFGF for 24 h did not lead to an increase in the release of lactate dehydrogenase in the culture supernatants compared to corresponding control incubations without any bFGF added. A significant increase in cytokine release was observed after the co-incubation of PBMCs with 100 or 200 ng of the same bFGF that was used for the animal experiments. Furthermore, the capacity of

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“…Injected BMP has been shown to enhance healing of segmental bone defects [13] and to speed the healing of fractures [14]. An interesting recent innovation is the combination of injected BMP-2 and bisphosphonate to simultaneously enhance bone formation and diminish resorption [15].…”

Section: Growth Areas and Problems Related To Shifting Boundariesmentioning

confidence: 99%

The future of MSK interventions

Rosenthal¹

2011

Skeletal Radiol

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A Single Percutaneous Injection of Recombinant Human Bone Morphogenetic Protein-2 Accelerates Fracture Repair

Cited by 178 publications

References 27 publications

Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells

Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells

Local application of basic fibroblast growth factor increases the risk of local infection after trauma: An in-vitro and in-vivo study in rats

The future of MSK interventions

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