Bone morphogenetic protein-2 and bone therapy: successes and pitfalls

Poon, Bonnie; Kha, Tram; Tran, Sarah; Dass, Crispin R.

doi:10.1111/jphp.12506

Cited by 87 publications

(84 citation statements)

References 46 publications

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“…5, 6 Although several signaling pathways can be potentially targeted to increase bone mineralization, their clinical use has been significantly limited due to their systemic non-skeletal effects. 7, 8 One strategy to overcome this limitation is the development of bone-specific biomaterials to target ubiquitous pathways exclusively in bone tissues. However despite these efforts, materials suitable for in vivo bone fluorescence imaging and/or targeting ubiquitous pathways in bone are extremely rare.…”

Section: Introductionmentioning

confidence: 99%

Carbon dots: promising biomaterials for bone-specific imaging and drug delivery

et al. 2017

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Bone-related diseases and dysfunctions are heavy burdens on our increasingly aged society. One important strategy to relieve this problem is through early detection and treatment of bone-related diseases. Towards this goal, there has been constant interest in developing novel bone-specific materials for imaging and drug delivery. Currently, however, materials that have high affinity and specificity towards bone are very limited. Carbon dots (C-dots) synthesized from carbon nanopowder bind to calcified bones in vivo with high affinity and specificity. In this study we show that bone binding is highly unique to a specific type of C-dots, and that this binding is non-toxic. Significantly, C-dots derived from other raw materials did not show any bone binding properties. These differences are attributed to differences in surface chemistry of C-dots preparations, highlighting the heterogeneous nature of C-dots. Importantly, bone-binding by carbon nanopowder derived C-dots are not significantly altered by chemical functionalization of their surface. These unique properties indicate the potential applications of carbon nanopowder-derived C-dots as highly bone-specific bioimaging agents and drug carriers.

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Section: Introductionmentioning

confidence: 99%

Carbon dots: promising biomaterials for bone-specific imaging and drug delivery

et al. 2017

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“…BMPs have a broad spectrum of biological functions, such as the regulation of cell proliferation and differentiation during development (21–23). In addition, some BMPs have been used in bone tissue engineering for various bone-associated diseases (24–26). Yet, the mechanism underlying these processes remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

Cao

Wei

Lian

et al. 2017

International Journal of Molecular Medicine

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Notch is an important pathway in that it regulates cell-to-cell signal transduction, which plays an essential role in skeletal remodeling. Bone morphogenetic protein (BMP)9 has been regarded as one of the most efficient BMPs by which to induce osteogenic differentiation in mesenchymal stem cells (MSCs). Understanding the interaction between Notch and BMP9 signaling is a critical issue for optimizing the application of MSCs and BMPs in bone tissue engineering. In the present study, we investigated the role of Notch signaling in the BMP9-induced osteogenic differentiation of MSCs. Our data demonstrated that Notch signaling obviously enhanced BMP9-induced osteogenic differentiation in MSCs in vitro and in vivo. Notch signaling augmented the activity of BMP9-induced BMP/Smad signaling and increased the gene expression of essential osteogenic factors induced by BMP9 in MSCs, such as runt-related transcription factor 2 (Runx2), type I collagen (Colla1) and inhibitor of differentiation (Id)1. We also found that Notch signaling promoted the expression of activin-like kinase 2 (ALK2) induced by BMP9, and the inhibitory effect of dnALK2 on BMP9-induced osteogenic differentiation was rescued by constitutive overexpression of Delta-like 1 (DLL1). Notch signaling also exhibited an apparent effect on the proliferation of mouse embryo fibroblasts (MEFs) during BMP9-induced osteogenic differentiation. These results indicate that Notch plays a significant role in mediating BMP9-induced osteogenic differentiation in MSCs, which may be partly regulated by upregulation of the expression of ALK2.

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“…Moreover, the high dose of BMP-2 has been reported to result in some side effects. 6 These drawbacks compromise the recombinant BMP-2 as a therapeutic agent for bone regeneration and drive the researchers to explore a small molecule to enhance bone formation.…”

Section: Introductionmentioning

confidence: 99%

Local controlled release of simvastatin and PDGF from core/shell microspheres promotes bone regeneration in vivo

Yan

Shen

et al. 2017

RSC Adv.

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aSimvastatin is demonstrated to be a potent stimulator for bone formation. However, a high dosage of simvastatin is required to induce bone regeneration in systematic administration, which may result in various side effects. Here we achieved the local administration of simvastatin through fabricating core/shell microspheres. Meanwhile, the addition of platelet derived growth factor (PDGF) encapsulated in core/shell microspheres was explored for a better outcome of bone regeneration. The microspheres composed of poly-L-lactide (PLLA) core and alginate shell were formulated via coaxial electrohydrodynamic atomization (CEHDA). The simvastatin and PDGF were incorporated in following models: (1) simvastatin was loaded in the core layer alone (core-simvastatin/shell, M1); (2) simvastatin was encapsulated in the core layer and PDGF was loaded into the shell layer (core-simvastatin/shell-PDGF, M2). Well-formed microspheres with distinct core-shell structures were successfully formulated. In vitro, simvastatin in the core layer displayed a near-zero-order release pattern within 40 days. In contrast, the release profile of PDGF in the shell layer was characterized with a strong initial burst release and being almost depleted in as early as 9 days. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed good biocompatibility with PLLA-alginate microspheres. In in vivo experiments, both the M1 and M2 groups showed greater new bone formation, with significantly increased bone mineral density (BMD), the ratio of mineralized bone volume of the defect tissue volume (BV/TV) and trabecula thickness (Tb.Th) of neogenesis bone, while little newly formed bone was found in sham surgery controls and blank microsphere groups. More importantly, the enhancement of bone regeneration was significantly greater in the M2 group. Thus, we suggested that the core/shell microspheres could be a promising delivery system for simvastatin combined with PDGF to improve bone regeneration.

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Bone morphogenetic protein-2 and bone therapy: successes and pitfalls

Cited by 87 publications

References 46 publications

Carbon dots: promising biomaterials for bone-specific imaging and drug delivery

Carbon dots: promising biomaterials for bone-specific imaging and drug delivery

Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling

Local controlled release of simvastatin and PDGF from core/shell microspheres promotes bone regeneration in vivo

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