Induction of Rapid Osteoblast Differentiation in Rat Bone Marrow Stromal Cell Cultures by Dexamethasone and BMP-2

Rickard, David J.; Sullivan, T.A.; Shenker, Bruce J.; Leboy, Phoebe S.; Kazhdan, Irene

doi:10.1006/dbio.1994.1022

Cited by 503 publications

(343 citation statements)

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“…The fibroblastic cell line, C3H10T1/2, established from an early mouse embryo, showed osteoinductive responses to rhBMP-2 (65,66). Rat and mouse bone marrow have shown responsiveness to rhBMP-2 by an increase in osteoblastic parameters (67,68), human bone marrow has shown an increase in osteoblastic parameters after rhBMP-2 or rhOP-1 treatment (69)(70)(71)(72). Treatment of primary human bone marrow stromal cells with rhOP-1 resulted in a concentration dependent increase of the osteogenic parameter alkaline phosphatase (72).…”

Section: Bmp and Demineralized Bone Matrixmentioning

confidence: 99%

Bone morphogenetic proteins in human bone regeneration

Groeneveld

Burgér

2000

European Journal of Endocrinology

358

217

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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...

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Section: Bmp and Demineralized Bone Matrixmentioning

confidence: 99%

Bone morphogenetic proteins in human bone regeneration

Groeneveld

Burgér

2000

European Journal of Endocrinology

358

217

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“…BMPs, and more specifically BMP-2, have potent effects in inducing osteoblast differentiation of different cell sources [14,19,20,46,53]. Several studies have demonstrated dexamethasone (DEX) as a non-GF can induce terminally differentiated osteoblasts [18,36,42].…”

Section: Introductionmentioning

confidence: 99%

Starch-poly-є-caprolactone Microparticles Reduce the Needed Amount of BMP-2

Balmayor

Feichtinger

Azevedo

et al. 2009

Clin Orthop Relat Res

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BMP-2 is currently administered clinically using collagen matrices often requiring large amounts of BMP-2 due to burst release over a short period of time. We developed and tested a novel injectable drug delivery system consisting of starch-poly-e-caprolactone microparticles for inducing osteogenesis and requiring smaller amounts of BMP-2. We evaluated BMP-2 encapsulation efficiency and the in vitro release profile by enzyme-linked immunosorbent assay. BMP-2 was rapidly released during the first 12 hours, followed by sustained release for up to 10 days. We then evaluated the osteogenic potential of dexamethasone (standard osteogenic induction agent) and BMP-2 after incorporation and during release using an osteo/myoblast cell line (C2C12). Alkaline phosphatase activity was increased by released BMP-2. Mineralization occurred after stimulation with BMP-2-loaded microparticles. A luciferase assay for osteocalcin promoter activity showed high levels of activity upon treatment with BMP-2-loaded microparticles. In contrast, no osteogenesis occurred in C2C12 cells using dexamethasone-loaded microparticles. However, human adipose stem cells exposed to the microparticles produced high amounts of alkaline phosphatase. The data suggest starch-poly-e-caprolactone microparticles are suitable carriers for the incorporation and controlled release of glucocorticoids and growth factors. Specifically, they reduce the amount of BMP-2 needed and allow more sustained osteogenic effects.

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“…These data suggest that repair and developmental processes are regulated through the coordinated actions of multiple BMPs instead of a single master BMP. Early experiments using recombinant human BMP-2, BMP-4 or BMP-7, demonstrated that these proteins have the ability to individually stimulate osteoblastic or chondrogenic phenotypic expression in various mesenchymal precursor cell lines [4,[8][9][10]. However, unlike the in vitro investigations, in vivo studies suggest that these factors function in a coordinated manner [7,11].…”

Section: Introductionmentioning

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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Induction of Rapid Osteoblast Differentiation in Rat Bone Marrow Stromal Cell Cultures by Dexamethasone and BMP-2

Cited by 503 publications

References 0 publications

Bone morphogenetic proteins in human bone regeneration

Bone morphogenetic proteins in human bone regeneration

Starch-poly-є-caprolactone Microparticles Reduce the Needed Amount of BMP-2

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

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