rhBMP2/7 Heterodimer: An Osteoblastogenesis Inducer of Not Higher Potency but Lower Effective Concentration Compared with rhBMP2 and rhBMP7 Homodimers

Zheng, Yuanna; Wu, Gang; Zhao, Juan; Wang, Lınhong; Sun, Ping; Gu, Zhenhua

doi:10.1089/ten.tea.2009.0312

Cited by 48 publications

(65 citation statements)

References 34 publications

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“…Recent study showed that the bone-inducing efficacy of BMP2/7 heterodimers was 15-20 fold more than that of BMP homodimers and BMP 2/7 heterodimers could be used in relatively low dosage without compromising its osseoinduction and bone regeneration efficacy 8) . Similarly, in our in vitro experiment, we found that rhBMP2/7 heterodimer induced cell migration with a significantly lower optimal concentration and higher peak effect and induced cell differentiation with significantly lower threshold concentrations than the respective homodimers 9) . Furthermore, our in vivo experiment using collagen sponges with low-dose (30 ng/ mL) BMP2/7 heterodimer to treat freshly created peri-implant bone defects on minipig's caldaria showed that BMP2/7 heterodimer induced new bone formation in a significantly higher quality and quantity in comparison to BMP2 and BMP7 homodimers by MicroCT and hard tissue slicing 10) .…”

Section: Introductionsupporting

confidence: 79%

“…It was reported that BMP2 could induce bone regeneration in CSD of rat calvaria at the dose of 30 to 240 ng/mm 3,30) . In our previous study, we found that the effective concentration of BMP2/7 to induce osteoblastogenesis was significantly lower than those of BMP2 and BMP7 homodimers 9) . Accordingly, 5.0 µg (equivalent to 30 ng/mm 3 in bone defects) BMP was used in this study.…”

Section: Discussionmentioning

confidence: 91%

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BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer

et al. 2012

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This study aimed to compare the effects of bone morphogenetic protein BMP2/7 heterodimer and BMP homodimers on bone regeneration in bone defects model. Identical peri-implant bone defects model were created using proper controls on the frontal skull in 18 minipigs. Collagen sponges with low-dose (30 ng/mL) BMP2/7 heterodimer, BMP2 or BMP7 homodimer were filled in the defects. New bone formation and the expression of type I collagen (Col1), alkaline phosphatase (ALP) and osteocalcin (OCN) were evaluated after 2, 3, and 6 weeks of implantation. BMP2/7 resulted in significantly higher new bone areas percentage in the defect region than BMP2 and BMP7 (p<0.05). Immunohistochemical staining of Col1, ALP and OCN was stronger in BMP2/7 group than BMP2, BMP7 and control group (p<0.05). These results demonstrate that BMP2/7 heterodimer is a stronger inducer of osteoblastogenesis and could be applied at low dose to reduce the cost and side effects of BMP homodimers.

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Section: Introductionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 91%

BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer

et al. 2012

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“…BMP2/BMP7 co-expression was chosen as a proof of concept in this study given its high osteoinductive potential in vitro and in vivo (Zhu et al, 2004;Kawai et al, 2006;Zheng et al, 2010), which has been shown to trigger expression of heterodimeric BMP2/7 (Kawai et al, 2009), a growth factor with high bioactivity (Israel et al, 1996;Zheng et al, 2010). Higher osteoinductive potential of BMP2/7 co-delivery in comparison with single gene delivery has been confirmed by ALP assays and osteocalcin reporter gene assays in vitro in this work.…”

Section: In Vitro Evaluation Constitutive Co-expression Systemsmentioning

confidence: 79%

Constitutive and inducible co-expression systems for non-viral osteoinductive gene therapy

Feichtinger

Hacobian²,

Hofmann³

et al. 2014

eCM

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Tissue regenerative gene therapy requires expression strategies that deliver therapeutic effective amounts of transgenes. As physiological expression patterns are more complex than high-level expression of a singular therapeutic gene, we aimed at constitutive or inducible co-expression of 2 transgenes simultaneously.Co-expression of human bone morphogenetic protein 2 and 7 (BMP2/7) from constitutively expressing and doxycycline inducible plasmids was evaluated in vitro in C2C12 cells with osteocalcin reporter gene assays and standard assays for osteogenic differentiation. The constitutive systems were additionally tested in an in vivo pilot for ectopic bone formation after repeated naked DNA injection to murine muscle tissue.Inductor controlled differentiation was demonstrated in vitro for inducible co-expression. Both co-expression systems, inducible and constitutive, achieved significantly better osteogenic differentiation than single factor expression. The potency of the constitutive co-expression systems was dependent on relative expression cassette topology. In vivo, ectopic bone formation was demonstrated in 6/13 animals (46 % bone formation efficacy) at days 14 and 28 in hind limb muscles as proven by in vivo µCT and histological evaluation.In vitro findings demonstrated that the devised single vector BMP2/7 co-expression strategy mediates superior osteoinduction, can be applied in an inductor controlled fashion and that its efficiency is dependent on expression cassette topology. In vivo results indicate that co-expression of BMP2/7 applied by non-viral naked DNA gene transfer effectively mediates bone formation without the application of biomaterials, cells or recombinant growth factors, offering a promising alternative to current treatment strategies with potential for clinical translation in the future.

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“…BMP-2/7 heterodimer was shown to be a more potent osteogenic factor than either homodimer in vitro 12 and can be used at a lower effective concentration. 13 In this study, we use the rhBMP-2/7 heterodimer to augment the osteointegration and graft healing of FlexBone.…”

mentioning

confidence: 99%

Elastomeric Osteoconductive Synthetic Scaffolds with Acquired Osteoinductivity Expedite the Repair of Critical Femoral Defects in Rats

Filion

Mason‐Savas

et al. 2011

Tissue Engineering Part A

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Regenerative medicine aspires to reduce reliance on or overcome limitations associated with donor tissuemediated repair. Structural bone allografts are commonly used in orthopedic surgery, with a high percentage of graft failure due to poor tissue integration. This problem is aggravated among elderly, those suffering from metabolic conditions, or those undergoing cancer therapies that compromise graft healing. Toward this end, we developed a synthetic graft named FlexBone, in which nanocrystalline hydroxyapatite (50 wt%) was structurally integrated with crosslinked poly(hydroxyethyl methacrylate) hydrogel, which provides dimensional stability and elasticity. It recapitulates the essential role of nanocrystalline hydroxyapatite in defining the osteoconductivity and biochemical microenvironment of bone because of its affinity for biomolecules. Here, we demonstrate that FlexBone effectively absorbed endogenously secreted signaling molecules associated with the inflammation/graft healing cascade upon being press-fit into a 5-mm rat femoral segmental defect. Further, when preabsorbed with a single dose of 400 ng recombinant human (rh) bone morphogenetic protein-2/7 heterodimer, it enabled the functional repair of the critical-sized defect by 8-12 weeks. FlexBone was stably encapsulated by the bridging bony callus and the FlexBone-callus interface was continuously remodeled. In summary, FlexBone combines the dimensional stability and osteoconductivity of structural bone allografts with desirable surgical compressibility and acquired osteoinductivity in an easy-to-fabricate and scalable synthetic biomaterial.

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rhBMP2/7 Heterodimer: An Osteoblastogenesis Inducer of Not Higher Potency but Lower Effective Concentration Compared with rhBMP2 and rhBMP7 Homodimers

Cited by 48 publications

References 34 publications

BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer

BMP2/7 heterodimer is a stronger inducer of bone regeneration in peri-implant bone defects model than BMP2 or BMP7 homodimer

Constitutive and inducible co-expression systems for non-viral osteoinductive gene therapy

Elastomeric Osteoconductive Synthetic Scaffolds with Acquired Osteoinductivity Expedite the Repair of Critical Femoral Defects in Rats

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