The Osteoinductive Effect of Controlled Bone Morphogenic Protein 2 Release Is Location Dependent.
Ontology highlight
ABSTRACT: Impact statement
The main challenge in bone morphogenic protein 2 (BMP-2)-based application lies in finding strategies to prolong its biologic activity as it has a short biological half-life. The present study uses a phosphate-modified oligo[(polyethylene glycol) fumarate] hydrogel that can be tuned to achieve differential release profiles of biologically active BMP-2 release. We demonstrate that this platform outperforms Infuse®, currently used in the clinic and that the osteoinductive effect of BMP-2 is location dependent. Altogether, this study stresses the importance of evaluating efficacy of bone tissue engineering strategies at an orthotopic location rather than subcutaneously. Even more so, it emphasizes the role of biomaterials as a scaffold to achieve proper bone tissue engineering.
SUBMITTER: Olthof MGL
PROVIDER: S-EPMC6388716 | biostudies-literature | 2019 Feb
REPOSITORIES: biostudies-literature
Publications
The Osteoinductive Effect of Controlled Bone Morphogenic Protein 2 Release Is Location Dependent.
Olthof Maurits G L MGL Lu Lichun L Tryfonidou Marianna A MA Loozen Loek D LD Pouran Behdad B Yaszemski Michael J MJ Meij Björn P BP Dhert Wouter J A WJA Alblas Jacqueline J Kempen Diederik H R DHR
Tissue engineering. Part A 20190130 3-4
<h4>Impact statement</h4>The main challenge in bone morphogenic protein 2 (BMP-2)-based application lies in finding strategies to prolong its biologic activity as it has a short biological half-life. The present study uses a phosphate-modified oligo[(polyethylene glycol) fumarate] hydrogel that can be tuned to achieve differential release profiles of biologically active BMP-2 release. We demonstrate that this platform outperforms Infuse<sup>®</sup>, currently used in the clinic and that the oste ...[more]
Similar Datasets
Project description:Bone morphogenetic proteins (BMPs) are probably the most important growth factors in bone formation and healing. However, the utilization of BMPs in clinical applications is mainly limited due to the protein poor solubility at physiological pH, rapid clearance and relatively short biological half-life. Herein, we develop degradable porous silicon (PSi)-based carriers for sustained delivery of BMP-2. Two different loading approaches are examined, physical adsorption and covalent conjugation, and their effect on the protein loading and release rate is thoroughly studied. The entrapment of the protein within the PSi nanostructures preserved its bioactivity for inducing osteogenic differentiation of rabbit bone marrow mesenchymal stems cells (BM-MSCs). BM-MSCs cultured with the BMP-2 loaded PSi carriers exhibit a relatively high alkaline phosphatase (ALP) activity. We also demonstrate that exposure of MSCs to empty PSi (no protein) carriers generates some extent of differentiation due to the ability of the carrier's degradation products to induce osteoblast differentiation. Finally, we demonstrate the integration of these promising BMP-2 carriers within a 3D-printed patient-specific implant, constructed of poly(caprolactone) (PCL), as a potential bone graft for critical size bone defects.
| S-EPMC6920899 | biostudies-literature
Project description:ObjectiveTo compare the direct osteogenic effect between placental growth factor-2 (PlGF-2) and bone morphogenic protein-2 (BMP-2).MethodsThree groups of PlGF-2/BMP-2-loaded heparin-N-(2-hydroxyl) propyl-3-trimethyl ammonium chitosan chloride (HTCC) nanocomplexes were prepared: those with 0.5 μg PlGF-2; with 1.0 μg BMP-2; and with 0.5 μg PlGF-2 combined with 1.0 μg BMP-2. The loading efficiencies and release profiles of these growth factors (GFs) in this nanocomplex system were quantified using enzyme-linked immunosorbent assay, their biological activities were evaluated using cell counting kit-8, cell morphology, and cell number counting assays, and their osteogenic activities were quantified using alkaline phosphatase and Alizarin Red S staining assays.ResultsThe loading efficiencies were more than 99% for the nanocomplexes loaded with just PlGF-2 and for those loaded with both PlGF-2 and BMP-2. For the nanocomplex loaded with just BMP-2, the loading efficiency was more than 97%. About 83%-84% of PlGF-2 and 89%-91% of BMP-2 were stably retained on the nanocomplexes for at least 21 days. In in vitro biological assays, PlGF-2 exhibited osteogenic effects comparable to those of BMP-2 despite its dose in the experiments being lower than that of BMP-2. Moreover, the results implied that heparin-based nanocomplexes encapsulating two GFs have enhanced potential in the enhancement of osteoblast function.ConclusionPlGF-2-loaded heparin-HTCC nanocomplexes may constitute a promising system for bone regeneration. Moreover, the dual delivery of PlGF-2 and BMP-2 appears to have greater potential in bone tissue regeneration than the delivery of either GFs alone.
| S-EPMC4809329 | biostudies-literature
Project description:BACKGROUND: Bone morphogenic proteins (BMPs) promote the survival of neurons, suggesting a therapeutic application of BMPs in the treatment of acute and chronic neurodegenerative disorders. However, the application of recombinant BMPs in vivo is limited by their short half-life. To provide a continuous supply for functionally active BMPs, we expressed BMP7, BMP2 and the BMP inhibitor Noggin under the control of rAAV vectors in vivo. For visual control of rAAV-mediated BMP (v-BMP) expression we fused the secreted morphogenic polypeptides and the fluorescent reporter protein Venus via the 'ribosomal skip' promoting 2A peptide-bridge. RESULTS: In primary cortical neurons, the rAAV-expressed morphogenic polypeptides were efficiently released from the 2A-Venus fusion precursors, were secreted, correctly processed and functionally active as shown by their effects on Smad phosphorylation in HeLa cells and in primary neurons, by the protection of v-BMP7-transduced primary cortical neurons against oxidative stress, and by the activation of BMP responsive GFP in v-BMP2 transduced reporter mice. In the stroke model of middle cerebral artery occlusion rAAV-transduced v-BMP7 reduced the infarct size in mice. CONCLUSION: Polycistronic rAAV vectors encoding secreted polypeptides and 2A-linked reporter proteins are potential novel therapeutic tools for the treatment of neurological and neurodegenerative diseases. Using this technique we documented that rAAV delivery of BMP7 reduced ischemic cell death in mice.
| S-EPMC3975265 | biostudies-literature
Project description:BMP7 is a growth factor playing pro- or anti-oncogenic roles in cancer in a cell type-dependent manner. We previously reported that the BMP7 gene is overexpressed in pheochromocytomas (PCCs) developing in MENX-affected rats and human patients. Here, analyzing a large cohort of PCC patients, we found that 72% of cases showed elevated levels of the BMP7 protein. To elucidate the role of BMP7 in PCC, we modulated its levels in PCC cell lines (overexpression in PC12, knockdown in MPC and MTT cells) and conducted functional assays. Active BMP signaling promoted cell proliferation, migration, and invasion, and sustained survival of MENX rat primary PCC cells. In PCC, BMP7 signals through the PI3K/AKT/mTOR pathway and causes integrin β1 up-regulation. Silencing integrin β1 in PC12 cells suppressed BMP7-mediated oncogenic features. Treatment of MTT cells with DMH1, a novel BMP antagonist, suppressed proliferation and migration. To verify the clinical applicability of our findings, we evaluated a dual PI3K/mTOR inhibitor (NVP-BEZ235) in MENX-affected rats in vivo. PCCs treated with NVP-BEZ235 had decreased proliferation and integrin β1 levels, and higher apoptosis. Altogether, BMP7 activates pro-oncogenic pathways in PCC. Downstream effectors of BMP7-mediated signaling may represent novel targets for treating progressive/inoperable PCC, still orphan of effective therapy.
| S-EPMC4770760 | biostudies-literature
Project description:Thanks to the precise control over their structural and functional properties, genetically engineered protein-based hydrogels have emerged as a promising candidate for biomedical applications. Given the growing demand for creating stimuli-responsive "smart" hydrogels, here we show the synthesis of entirely protein-based photoresponsive hydrogels by covalently polymerizing the adenosylcobalamin (AdoB12)-dependent photoreceptor C-terminal adenosylcobalamin binding domain (CarHC) proteins using genetically encoded SpyTag-SpyCatcher chemistry under mild physiological conditions. The resulting hydrogel composed of physically self-assembled CarHC polymers exhibited a rapid gel-sol transition on light exposure, which enabled the facile release/recovery of 3T3 fibroblasts and human mesenchymal stem cells (hMSCs) from 3D cultures while maintaining their viability. A covalently cross-linked CarHC hydrogel was also designed to encapsulate and release bulky globular proteins, such as mCherry, in a light-dependent manner. The direct assembly of stimuli-responsive proteins into hydrogels represents a versatile strategy for designing dynamically tunable materials.
| S-EPMC5468657 | biostudies-literature
Project description:We have recently fabricated biodegradable polyHIPEs as injectable bone grafts and characterized the mechanical properties, pore architecture, and cure rates. In this study, calcium phosphate nanoparticles and demineralized bone matrix (DBM) particles were incorporated into injectable polyHIPE foams to promote osteoblastic differentiation of mesenchymal stem cells (MSCs). Upon incorporation of each type of particle, stable monoliths were formed with compressive properties comparable to control polyHIPEs. Pore size quantification indicated a negligible effect of all particles on emulsion stability and resulting pore architecture. Alizarin red calcium staining illustrated the incorporation of calcium phosphate particles at the pore surface, while picrosirius red collagen staining illustrated collagen-rich DBM particles within the monoliths. Osteoinductive particles had a negligible effect on the compressive modulus (?30?MPa), which remained comparable to human cancellous bone values. All polyHIPE compositions promoted human MSC viability (?90%) through 2 weeks. Furthermore, gene expression analysis indicated the ability of all polyHIPE compositions to promote osteogenic differentiation through the upregulation of bone-specific markers compared to a time zero control. These findings illustrate the potential for these osteoinductive polyHIPEs to promote osteogenesis and validate future in vivo evaluation. Overall, this work demonstrates the ability to incorporate a range of bioactive components into propylene fumarate dimethacrylate-based injectable polyHIPEs to increase cellular interactions and direct specific behavior without compromising scaffold architecture and resulting properties for various tissue engineering applications.
| S-EPMC4800270 | biostudies-literature
Project description:Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3(+) regulatory T-cells (T(R)) were identified as the major obstacle to effective cancer immunotherapy. The abundance of these cells in peripheral blood is increased in patients with multiple types of cancer and their prevalence among tumor-infiltrating lymphocytes correlated with poor clinical prognosis. In contrast, removal or inactivation of T(R) cells led to enhanced anti-tumor immune response and better efficacy of cancer vaccines. This study reports that Bone Morphogenic Protein Receptor 1? (BMPR1?, Alk-3) is expressed by activated effector CD4(+) and T(R) cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-? family of cytokines that also include TGF? and activins. BMPs play crucial roles in embryonic development, tissue differentiation and homeostasis, and development of cancer. It was demonstrated that BMPs and activins synergize with TGF? to regulate thymic T-cell development, maintain T(R) cells, and control peripheral tolerance. Inactivation of BMPR1? in T-cells results in impaired thymic and peripheral generation of T(R) cells. BMPR1?-deficient activated T-cells produced a higher level of interferon (IFN)-? than BMPR1?-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1? in T-cells and tumors had few infiltrating TR cells and a higher proportion of CD8(+) T-cells than wild-type mice.
| S-EPMC4464667 | biostudies-literature
Project description:AimsAtherosclerosis develops near branches and bends of arteries that are exposed to disturbed blood flow which exerts low wall shear stress (WSS). These mechanical conditions alter endothelial cells (EC) by priming them for inflammation and by inducing turnover. Homeobox (Hox) genes are developmental genes involved in the patterning of embryos along their anterior-posterior and proximal-distal axes. Here we identified Hox genes that are regulated by WSS and investigated their functions in adult arteries.Methods and resultsEC were isolated from inner (low WSS) and outer (high WSS) regions of the porcine aorta and the expression of Hox genes was analysed by quantitative real-time PCR. Several Hox genes (HoxA10, HoxB4, HoxB7, HoxB9, HoxD8, HoxD9) were significantly enriched at the low WSS compared to the high WSS region. Similarly, studies of cultured human umbilical vein EC (HUVEC) or porcine aortic EC revealed that the expression of multiple Hox genes (HoxA10, HoxB9, HoxD8, HoxD9) was enhanced under low (4?dyn/cm2) compared to high (13?dyn/cm2) WSS conditions. Gene silencing studies identified Hox genes (HoxB9, HoxD8, HoxD9) that are positive regulators of inflammatory molecule expression in EC exposed to low WSS, and others (HoxB9, HoxB7, HoxB4) that regulated EC turnover. We subsequently focused on HoxB9 because it was strongly up-regulated by low WSS and, uniquely, was a driver of both inflammation and proliferation. At a mechanistic level, we demonstrate using cultured EC and murine models that bone morphogenic protein 4 (BMP4) is an upstream regulator of HoxB9 which elicits inflammation via induction of numerous inflammatory mediators including TNF and downstream NF-?B activation. Moreover, the BMP4-HoxB9-TNF pathway was potentiated by hypercholesterolaemic conditions.ConclusionsLow WSS induces multiple Hox genes that control the activation state and turnover of EC. Notably, low WSS activates a BMP4-HoxB9-TNF signalling pathway to initiate focal arterial inflammation, thereby demonstrating integration of the BMP and Hox systems in vascular pathophysiology.
| S-EPMC7243277 | biostudies-literature
Project description:The Bmp2 and Bmp4 expressed in root mesenchyme were essential for the patterning and cellular differentiation of tooth root. The role of the epithelium-derived Bmps in tooth root development, however, had not been reported. In this study, we found that the double abrogation of Bmp2 and Bmp4 from mouse epithelium caused short root anomaly (SRA). The K14-cre;Bmp2 f/f ;Bmp4 f/f mice exhibited a persistent Hertwig's Epithelial Root Sheath (HERS) with the reduced cell death, and the down-regulated BMP-Smad4 and Erk signaling pathways. Moreover, the Shh expression in the HERS, the Shh-Gli1 signaling, and Nfic expression in the root mesenchyme of the K14-cre;Bmp2 f/f ;Bmp4 f/f mice were also decreased, indicating a disrupted epithelium- mesenchyme interaction between HERS and root mesenchyme. Such disruption suppressed the Osx and Dspp expression in the root mesenchyme, indicating an impairment on the differentiation and maturation of root odontoblasts. The impaired differentiation and maturation of root odontoblasts could be rescued partially by transgenic Dspp. Therefore, although required in a low dosage and with a functional redundancy, the epithelial Bmp2 and Bmp4 were indispensable for the HERS degeneration, as well as the differentiation and maturation of root mesenchyme.
| S-EPMC8415269 | biostudies-literature
Project description:It has been long believed that the anteroposterior (A-P) and dorsoventral (D-V) axes in the developing retina are determined independently and also that the retinotectal projection along the two axes is controlled independently. However, we recently demonstrated that misexpression of Ventroptin, a bone morphogenic protein (BMP) antagonist, in the developing chick retina alters the retinotectal projection not only along the D-V (or mediolateral) axis but also along the A-P axis. Moreover, the dorsal-high expression of BMP4 is relieved by the dorsotemporal-high expression of BMP2 at embryonic day 5 (E5) in the retina, during which Ventroptin continuously counteracts the two BMPs keeping on the countergradient expression pattern, respectively. Here, we show that the topographic molecules so far reported to have a gradient only along the D-V axis and ephrin-A2 so far only along the A-P axis are both controlled by the BMP signal, and that they are expressed in a gradient manner along the tilted axis from E6 on in the developing chick retina: the expression patterns of these oblique-gradient molecules are all changed, when BMP2 expression is manipulated in the developing retina. Furthermore, in both BMP2 knockdown embryos and ephrin-A2-misexpressed embryos, the retinotectal projection is altered along the two orthogonal axes. The expressional switching from BMP4 to BMP2 thus appears to play a key role in the retinal patterning and topographic retinotectal projection by tilting the D-V axis toward the posterior side during retinal development. Our results also indicate that BMP2 expression is essential for the maintenance of regional specificity along the revised D-V axis.
| S-EPMC6674735 | biostudies-literature