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Behnoush Khorsand, Satheesh Elangovan, Liu Hong, Alexander Dewerth, Michael S D Kormann, Aliasger K Salem
Employing cost-effective biomaterials to deliver chemically modified ribonucleic acid (cmRNA) in a controlled manner addresses the high cost, safety concerns, and lower transfection efficiency that exist with protein and gene therapeutic approaches. By eliminating the need for nuclear entry, cmRNA therapeutics can potentially overcome the lower transfection efficiencies associated with non-viral gene delivery systems. Here, we investigated the osteogenic potential of cmRNA-encoding BMP-9, in comparison to cmRNA-encoding BMP-2...
January 10, 2017: AAPS Journal
Maryna Bondarava, Chiara Cattaneo, Bin Ren, Wolfgang E Thasler, Volkmar Jansson, Peter E Müller, Oliver B Betz
Conventional bone tissue engineering approaches require isolation and in vitro propagation of autologous cells, followed by seeding on a variety of scaffolds. Those protracted procedures impede the clinical applications. Here we report the transdifferentiation of human fat tissue fragments retrieved from subcutaneous fat into tissue with bone characteristics in vitro without prior cell isolation and propagation. 3D collagen-I cultures of human fat tissue were cultivated either in growth medium or in osteogenic medium (OM) with or without addition of Bone Morphogenetic Proteins (BMPs) BMP-2, BMP-7 or BMP-9...
January 5, 2017: Scientific Reports
Martin H Voss, Rupal S Bhatt, Elizabeth R Plimack, Brian I Rini, Robert S Alter, J Thaddeus Beck, Dawn Wilson, Xiaosha Zhang, Musa Mutyaba, Chad Glasser, Kenneth M Attie, Matthew L Sherman, Shuchi S Pandya, Michael Atkins
PURPOSE: Activin receptor-like kinase 1 (ALK1) is a novel target in angiogenesis. Concurrent targeting of ALK1 and vascular endothelial growth factor (VEGF) signaling results in augmented inhibition of tumor growth in renal cell carcinoma (RCC) xenograft models. Dalantercept is an ALK1 receptor-fusion protein that acts as a ligand trap for bone morphogenetic proteins (BMP) 9 and 10. The DART Study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of dalantercept plus axitinib in patients with advanced RCC and determined the optimal dose for further testing...
December 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yong Luo, Ling Li, Xiaohui Xu, Tong Wu, Mengliu Yang, Cheng Zhang, Huaming Mou, Tingting Zhou, Yanjun Jia, Chenrongrong Cai, Hua Liu, Gangyi Yang, Xianxiang Zhang
Bone morphogenetic protein 9 (BMP-9) has been demonstrated to improve glucose homoeostasis in diabetic mice. However, no report has demonstrated the relationship of circulating BMP-9 levels with insulin resistance (IR) or Type 2 diabetes mellitus (T2DM) in humans. The objective of the present study was to investigate the relationship between BMP-9 and IR in cross-sectional and interventional studies. Circulating BMP-9 levels were analysed by ELISA in 280 well-characterized individuals. Two-hour oral glucose tolerance test (OGTT) and euglycaemic-hyperinsulinaemic clamp (EHC) were performed in 20 healthy subjects...
February 1, 2017: Clinical Science (1979-)
Yahya Açil, Amir Alexander Ghoniem, Aydin Gülses, Tobias Kisch, Felix Stang, Jörg Wiltfang, Matthias Gierloff
Recent studies indicated a lower osteogenic differentiation potential of adipose tissue-derived stromal cells (ASCs) compared to bone marrow derived mesenchymal stromal cells. The aim of this study was to evaluate the effects of potent combinations of highly osteogenic bone morphogenetic proteins (BMPs) in order to enhance the osteogenic differentiation potential of ASCs. Human ASCs were cultured for 10 days in the presence of osteogenic medium consisting of dexamethasone, ß-glycerophosphate and ascorbat-2-phosphate (OM) supplemented with BMP-2, BMP-6, BMP-9+IGF-2 and BMP-2,-6,-9 (day 1+2: 50 ng/ml, days 3-6: 100 ng/ml, days 7-10: 200 ng/ml)...
January 2017: Journal of Cranio-maxillo-facial Surgery
Bo Li, Yuehua Yang, Shengdan Jiang, Binbin Ni, Ke Chen, Leisheng Jiang
Following the publication of this article, an interested reader drew to our attention an anomaly associated with the presentation of the western blots in Fig. 4B and C. These contained the same GAPDH control data, even though Fig. 4B and C were intended to show the inhibition of osteosarcoma cell migration by a recombinant adenovirus (ad) expressing bone morphogenetic protein 9 (adBMP-9) in two different cell lines, MG-63 and HOS, respectively. After having re-examined our original data, we realize that the same GAPDH control bands were inadvertently selected for Fig...
November 2016: International Journal of Oncology
Hai Li, Dahang Zhao, Shengjing Wang, Jing Ding, Li Zhao
It has been confirmed that bone morphogenetic protein-9 (BMP-9) promotes the differentiation of osteoblasts. However, the ways in which BMP‑9 exerts its effects on the differentiation of osteoclasts and bone resorption remain to be elucidated. The present study was designed to investigate the roles and the molecular mechanism of BMP‑9 on the proliferation and differentiation of osteoclast precursors in vitro. Mouse spleen macrophages (RAW 264.7 cells) were cultured in the presence of receptor activator for nuclear factor‑κb ligand (RANKL) in vitro...
November 2016: Molecular Medicine Reports
Toshiaki Nakamura, Yoshinori Shirakata, Yukiya Shinohara, Richard J Miron, Kirara Furue, Kazuyuki Noguchi
OBJECTIVES: It has been reported that bone morphogenetic protein (BMP)-9 has potent osteoinductive properties among the BMP family by adenovirus-transfection experiments. We very recently reported that absorbable collagen sponge (ACS) as a carrier for recombinant human (rh) BMP-9, compared with chitosan sponge, was suitable for inducing bone healing/regeneration by BMP-9 in a rat calvarial defect model. The aim of this study was to evaluate different doses of rhBMP-9/ACS on new bone formation in rat critical size calvarial defects...
October 11, 2016: Clinical Oral Investigations
Jae Woo Jung, So-Mi Yoon, Subin Kim, Yun-Hui Jeon, Byung-Hak Yoon, Su-Geun Yang, Min Kyoung Kim, Senyon Choe, Mario Meng-Chiang Kuo
The biological role of BMP-9 signaling in liver cancer remains dubious. To explore the potential use of BMP-9 signaling for anti-cancer therapy, we used recombinant human BMP-9, which we referred to as MB109, to study the effect on growth of fifteen hepatocellular carcinoma (HCC) cell lines. MB109 effectively inhibits the proliferation of nine HCC cells in vitro. The anti-proliferative effect was found to be induced by turning on p21 signaling, which caused survivin suppression and G0/G1 cell cycle arrest. ID3 was identified to be the mediator of the MB109-induced p21 expression...
September 16, 2016: Oncotarget
Sarah L Appleby, Claudia-Gabriela Mitrofan, Alexi Crosby, Kim Hoenderdos, Katharine Lodge, Paul D Upton, Clara M Yates, Gerard B Nash, Edwin R Chilvers, Nicholas W Morrell
Bone morphogenetic protein (BMP)9 is a circulating growth factor that is part of the TGF-β superfamily and is an essential regulator of vascular endothelial homeostasis. Previous studies have suggested a role for BMP9 signaling in leukocyte recruitment to the endothelium, but the directionality of this effect and underlying mechanisms have not been elucidated. In this study, we report that BMP9 upregulates TLR4 expression in human endothelial cells and that BMP9 pretreatment synergistically increases human neutrophil recruitment to LPS-stimulated human endothelial monolayers in an in vitro flow adhesion assay...
October 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Amaya García de Vinuesa, Matteo Bocci, Kristian Pietras, Peter Ten Dijke
Angiogenesis is a hallmark of cancer and is now a validated therapeutic target in the clinical setting. Despite the initial success, anti-angiogenic compounds impinging on the vascular endothelial growth factor (VEGF) pathway display limited survival benefits in patients and resistance often develops due to activation of alternative pathways. Thus, finding and validating new targets is highly warranted. Activin receptor-like kinase (ALK)1 is a transforming growth factor beta (TGF-β) type I receptor predominantly expressed in actively proliferating endothelial cells (ECs)...
August 15, 2016: Biochemical Society Transactions
Wei Li, Richard M Salmon, He Jiang, Nicholas W Morrell
Bone morphogenetic protein (BMP)9 and BMP10 are high affinity ligands for activin receptor-like kinase 1 (ALK1), a type I BMP receptor mainly expressed on vascular endothelial cells (ECs). ALK1-mediated BMP9/BMP10 signalling pathways have emerged as essential in EC biology and in angiogenesis. Several genetic mutations in the genes encoding the ligands and receptors of this pathway have been reported in two cardiovascular diseases, pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT)...
August 15, 2016: Biochemical Society Transactions
Marc-Antoine Lauzon, Olivier Drevelle, Alex Daviau, Nathalie Faucheux
The bone morphogenetic proteins (BMPs), which are involved in bone formation and repair, play an important role in tissue engineering. For example, BMP-9 and BMP-2, which are members of different BMP subfamilies, are osteoinductive factors. However, several studies have recently shown that BMP-9 is more osteogenic than BMP-2. We have previously shown that fetal bovine serum (FBS) strongly enhances the osteoblast differentiation of murine preosteoblasts (MC3T3-E1) to BMP-9 but not to BMP-2. This effect is mimicked by IGF-2, which primarily activates the PI3K/Akt pathway, but how Akt phosphorylation sites are implicated in such differentiation is unclear...
September 2016: Tissue Engineering. Part A
Xuelu Wang, Gerhard Fischer, Marko Hyvönen
Activins are growth factors with multiple roles in the development and homeostasis. Like all TGF-β family of growth factors, activins are synthesized as large precursors from which mature dimeric growth factors are released proteolytically. Here we have studied the activation of activin A and determined crystal structures of the unprocessed precursor and of the cleaved pro-mature complex. Replacing the natural furin cleavage site with a HRV 3C protease site, we show how the protein gains its bioactivity after proteolysis and is as active as the isolated mature domain...
2016: Nature Communications
Guangde Zhang, Chengshuai Su, Xia Jin, Shimao Yang, Dianji Fang, Yanwei Guo
OBJECTIVE: To investigate the effect of recombinant adenovirus-mediated bone morphogenetic protein 9 (BMP-9) and erythropoietin (EPO) genes co-transfection on osteogenic differentiation of adipose-derived stem cells (ADSCs) in vitro. METHODS: The inguinal adipose tissue was harvested from 4-month-old New Zealand rabbits, ADSCs were isolated with enzyme digestion and adherence method, and multipotent differentiation capacity was identified. The 3rd generation ADSCs were divided into 5 groups: normal cells (group A), empty plasmid control group (group B), BMP-9 or EPO recombinant adenovirus transfected cells (groups C and D), BMP-9 and EPO recombinant adenovirus co-transfected cells (group E)...
March 2016: Chinese Journal of Reparative and Reconstructive Surgery
Miao Wang, Nan Wang, Zhengxue Quan, Xiaoji Luo
OBJECTIVE: To investigate the effect of Notch signaling pathway important target Hey1 expression on the differentiation and proliferation of C3H10T1/2 cells induced by bone morphogenetic protein 9 (BMP-9). METHODS: Hey1 lentivirus and Hey1 short hairpin RNA lentivirus were constructed and used to infect C3H10T1/2 cells to change the expression level of Hey1 in C3H10T1/2 cells. C3H10T1/2 cells infected with LV-Blank (empty plasmid) as control. The Hey1 expression levels of different groups were detected by fluorescence microscope, real-time fluorescence quantitative PCR, and Western blot...
March 2016: Chinese Journal of Reparative and Reconstructive Surgery
Xiaoyan Ren, Daniel W Weisgerber, David Bischoff, Michael S Lewis, Russell R Reid, Tong-Chuan He, Dean T Yamaguchi, Timothy A Miller, Brendan A C Harley, Justine C Lee
Engineering the osteochondral junction requires fabrication of a microenvironment that supports both osteogenesis and chondrogenesis. Multiphasic scaffold strategies utilizing a combination of soluble factors and extracellular matrix components are ideally suited for such applications. In this work, the contribution of an osteogenic nanoparticulate mineralized glycosaminoglycan scaffold (MC-GAG) and a dually chondrogenic and osteogenic growth factor, BMP-9, in the differentiation of primary human mesenchymal stem cells (hMSCs) is evaluated...
July 2016: Advanced Healthcare Materials
Yukiya Shinohara, Toshiaki Nakamura, Yoshinori Shirakata, Kazuyuki Noguchi
The aim of this study was to examine the effects of recombinant human BMP-9 (rhBMP-9) with chitosan sponge (ChiS) or absorbable collagen sponge (ACS) on bone formation in rat calvarial defects. The defects were treated by one of the following implantations: ChiS, rhBMP-9/ChiS, ACS, rhBMP-9/ACS and no implantation. The animals were euthanized at 8 weeks for histological evaluation. The percentage of defect closure (DC) in the rhBMP-9/ACS group was significantly greater than that in the ACS group. The rhBMP-9/ACS group demonstrated the highest level of DC among all the groups...
2016: Dental Materials Journal
Xiaoen Wang, Nicolas Solban, Prateek Khanna, Marcella Callea, Jiaxi Song, David C Alsop, R Scott Pearsall, Michael B Atkins, James W Mier, Sabina Signoretti, Marat Alimzhanov, Ravi Kumar, Manoj K Bhasin, Rupal S Bhatt
Treatment of metastatic renal cell carcinoma (mRCC) with agents that block signaling through vascular endothelial growth factor receptor 2 (VEGFR2) induces disease regression or stabilization in some patients; however, these responses tend to be short-lived. Therefore, development of combination therapies that can extend the efficacy of VEGFR antagonists in mRCC remains a priority.We studied murine xenograft models of RCC that become refractory to treatment with the VEGFR tyrosine kinase inhibitor (TKI) sunitinib...
July 5, 2016: Oncotarget
Sooho Kim, Senyon Choe, Dong Kun Lee
Although BMP-9 has been reported to induce browning of white adipose tissues (WATs) and suppress high fat diet-induced obesity, detailed molecular mechanism needs to be further elucidated. We report here that administration of MB109, a recombinant derivative of human BMP-9, into obese mice enhanced gene expression of fibroblast growth factor 21 (FGF21), a metabolic regulator, and alleviates a spectrum of pathological symptoms due to high fat diet-induced obesity. In addition, periodical injection of MB109 (500μg/kg/week) reduced an amount of lipid droplets in the liver, serum levels of alanine aminotransferase (ALT), and total cholesterol...
July 2016: Biochimica et Biophysica Acta
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