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Nikolas M Eleftheriou, Jonas Sjölund, Matteo Bocci, Eliane Cortez, Se-Jin Lee, Sara I Cunha, Kristian Pietras
Angiogenesis occurs early in tumor development, sustains primary tumor growth and provides a route for metastatic escape. The TGF-β family receptors modulate angiogenesis via endothelial-cell specific pathways. Here we investigate the interaction of two such receptors, ALK1 and endoglin, in pancreatic neuroendocrine tumors (PanNET). Independently, ALK1 and endoglin deficiencies exhibited genetically divergent phenotypes, while both highly correlate to an endothelial metagene in human and mouse PanNETs. A concurrent deficiency of both receptors synergistically decreased tumor burden to a greater extent than either individual knockdown...
October 12, 2016: Oncotarget
Shun Lu, Jing Wang, Jixing Ye, Yulong Zou, Yunxiao Zhu, Qiang Wei, Xin Wang, Shengli Tang, Hao Liu, Jiaming Fan, Fugui Zhang, Evan M Farina, Maryam M Mohammed, Dongzhe Song, Junyi Liao, Jiayi Huang, Dan Guo, Minpeng Lu, Feng Liu, Jianxiang Liu, Li Li, Chao Ma, Xue Hu, Michael J Lee, Russell R Reid, Guillermo A Ameer, Dongsheng Zhou, Tongchuan He
Regenerative medicine and bone tissue engineering using mesenchymal stem cells (MSCs) hold great promise as an effective approach to bone and skeletal reconstruction. While adipose tissue harbors MSC-like progenitors, or multipotent adipose-derived cells (MADs), it is important to identify and characterize potential biological factors that can effectively induce osteogenic differentiation of MADs. To overcome the time-consuming and technically challenging process of isolating and culturing primary MADs, here we establish and characterize the reversibly immortalized mouse multipotent adipose-derived cells (iMADs)...
2016: American Journal of Translational Research
Byeong-Joo Noh, Youn Wha Kim, Yong-Koo Park
Heterotopic ossification occurring to low-grade appendiceal mucinous neoplasm (LAMN) (pseudomyxoma peritonei) is extremely rare. The pathogenetic mechanism of the tumor-related heterotopic bone formation remains as yet unconfirmed. Here, we describe a rare case of LAMN with ossification in a 72-year-old woman, and concentrate on the etiology of heterotopic ossification by the immunohistochemical evaluation of the novel markers such as BMP9, osteocalcin, and osteopontin. BMP9 is one of the most effective osteogenetic proteins...
September 22, 2016: Pathology, Research and Practice
J Zhang, J H Liang, J G Huang
Osteosarcoma (OS) causes millions of death worldwide and, since there is no effective therapy, it is necessary to identify the molecular mechanism of OS, which can direct the development of new therapies. This study investigated the role of bone morphogenetic protein 9 (BMP9), a member of the transforming growth factor (TGF)-β family, in OS development. This study first examined BMP9 expression in tissue from OS patients and normal subjects. The OS cell line (MG63) and tumor cells from OS patients were then transfected with BMP9 and cell proliferation and apoptosis were assessed...
September 16, 2016: Genetics and Molecular Research: GMR
Masako Fujioka-Kobayashi, Benoit Schaller, Nikola Saulacic, Yufeng Zhang, Richard J Miron
Within the past years, BMP9 has been characterized as one of the most osteogenic bone-inducers among the BMP family, however up until recently, BMP9 has only been available through adenovirus transfection experiments(gene therapy) not approved for clinical use. The aim of this study was to investigate recombinant rhBMP9 versus rhBMP2 at 2 concentrations (10ng/mL and 100ng/mL) in combination with 2 bone grafts: 1)a natural bone mineral(NBM) without collagen versus 2)a novel NBM integrated with atelo-collagen type I(NBM-Col)...
October 3, 2016: Journal of Biomedical Materials Research. Part A
Claudio A Franco, Holger Gerhardt
Bone morphogenic proteins (BMPs) and blood flow regulate vascular remodeling and homeostasis. In this issue, Baeyens et al. (2016. J. Cell Biol show that blood flow sensitizes endothelial cells to BMP9 signaling by triggering Alk1/ENG complexing to suppress cell proliferation and to recruit mural cells, thereby establishing endothelial quiescence.
September 26, 2016: Journal of Cell Biology
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...
September 19, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Nicolas Baeyens, Bruno Larrivée, Roxana Ola, Brielle Hayward-Piatkowskyi, Alexandre Dubrac, Billy Huang, Tyler D Ross, Brian G Coon, Elizabeth Min, Maya Tsarfati, Haibin Tong, Anne Eichmann, Martin A Schwartz
Morphogenesis of the vascular system is strongly modulated by mechanical forces from blood flow. Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal-dominant disease in which arteriovenous malformations and telangiectasias accumulate with age. Most cases are linked to heterozygous mutations in Alk1 or Endoglin, receptors for bone morphogenetic proteins (BMPs) 9 and 10. Evidence suggests that a second hit results in clonal expansion of endothelial cells to form lesions with poor mural cell coverage that spontaneously rupture and bleed...
September 26, 2016: Journal of Cell Biology
Wendong Ruan, Yuan Xue, Yaqi Zong, Chao Sun
In the present study, third‑generation autologous‑inactivated bone morphogenic protein 2 (BMP2), BMP4, BMP6, BMP7, BMP9 and Wnt3a lentiviral vectors were constructed and integrated into the genome of MC3T3‑E1 murine mesenchymal stem cells (MMSCs) to produce osteoinductive factor gene‑modified MMSCs. The transfection efficiency of each osteoinductive factor was then determined by detecting the expression levels of runt related transcription factor 2 (Runx2) mRNA. The cotransfection with combinations of two lentiviruses was performed, and the expression levels of bone γ‑carboxyglutamate protein and alkaline phosphatase in the MC3T3‑E1 cell culture supernatant were detected...
September 12, 2016: Molecular Medicine Reports
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
Kalonji Ntumba, Naoufal Akla, S Paul Oh, Anne Eichmann, Bruno Larrivée
Age-related macular degeneration (AMD) is the leading cause of blindness in aging populations of industrialized countries. The drawbacks of inhibitors of vascular endothelial growth factor (VEGFs) currently used for the treatment of AMD, which include resistance and potential serious side-effects, require the identification of new therapeutic targets to modulate angiogenesis. BMP9 signaling through the endothelial Alk1 serine-threonine kinase receptor modulates the response of endothelial cells to VEGF and promotes vessel quiescence and maturation during development...
August 10, 2016: Oncotarget
Ling Yu, Mingquan Yan, Jennifer Simkin, Paulina D Ketcham, Eric Leininger, Manjong Han, Ken Muneoka
The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti-angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551-559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation...
June 2014: Regeneration
Byeong-Joo Noh, Youn Wha Kim, Yong-Koo Park
Heterotopic ossification occurring in colon cancer is an exceedingly rare event. The pathogenetic mechanism of tumor-related heterotopic bone formation remains unclear. Herein, we describe a rare case of colon cancer with ossification in a 76-year-old woman. We also highlight the etiology of heterotopic ossification by immunohistochemical evaluation of novel markers such as bone morphogenetic protein 9 (BMP9), osteocalcin, osteopontin, and β-catenin. BMP9 is one of the most potent osteogenetic BMPs. However, no previous research has been performed concerning BMP9 in heterotopic ossification arising in colon cancer...
July 2016: Annals of Clinical and Laboratory Science
Vrinda Sreekumar, Romina Haydeé Aspera-Werz, Gauri Tendulkar, Marie Karolina Reumann, Thomas Freude, Katja Breitkopf-Heinlein, Steven Dooley, Stefan Pscherer, Björn Gunnar Ochs, Ingo Flesch, Valeska Hofmann, Andreas Klaus Nussler, Sabrina Ehnert
Promotion of rhBMP2 and rhBMP7 for the routine use to support fracture healing has been hampered by high costs, safety concerns and reasonable failure rates, imposing restrictions in its clinical use. Since there is little debate regarding its treatment potential, there is rising need for a better understanding of the mode of action of these BMPs to overcome its drawbacks and promote more efficacious treatment strategies for bone regeneration. Recently, BMP9, owing to its improved osteogenic potential, is gaining attention as a promising therapeutic alternative...
July 9, 2016: Archives of Toxicology
Songhua Fang, Shuxia Liu, Yuan Chen
Objective To investigate the role of β-catenin in the differentiation of C3H10T1/2 cells into cardiomyocyte-like cells induced by bone morphogenetic protein 9 (BMP9). Methods C3H10T1/2 cells were transfected with the recombinant adenovirus expressing BMP9 (Ad-BMP9) and differentiated into cardiomyocytes in vitro for up to 21 days. The activated level of β-catenin in the cells after cultivated with Ad-BMP9 and different concentrations of β-catenin specific inhibitor XAV-939 was detected by Western blotting...
June 2016: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
José M Muñoz-Félix, Cristina Cuesta, Nuria Perretta-Tejedor, Mariela Subileau, Francisco J López-Hernández, José M López-Novoa, Carlos Martínez-Salgado
Upregulated synthesis of extracellular matrix (ECM) proteins by myofibroblasts is a common phenomenon in the development of fibrosis. Although the role of TGF-β in fibrosis development has been extensively studied, the involvement of other members of this superfamily of cytokines, the bone morphogenetic proteins (BMPs) in organ fibrosis has given contradictory results. BMP9 is the main ligand for activin receptor-like kinase-1 (ALK1) TGF-β1 type I receptor and its effect on fibrosis development is unknown...
September 2016: Cellular Signalling
Jing Wang, Yaguang Weng, Minghao Zhang, Ya Li, Mengtian Fan, Yangliu Guo, Yanting Sun, Wang Li, Qiong Shi
Bone is the most common distant metastatic site of lung cancer, and is particularly prone to osteolytic damage. Soluble factors secreted from bone marrow-derived cells and tumor cells contribute to the growth and metastasis of cancer cells, and enhance osteolytic damage. BMP9, as the most powerful osteogenetic factor of the bone morphogenetic protein (BMP) family, can regulate the development of various tumors. However, the effects and underlying mechanisms of BMP9 in regards to lung cancer and the bone metastatic microenvironment are poorly understood...
July 2016: Oncology Reports
Jixing Ye, Jing Wang, Yunxiao Zhu, Qiang Wei, Xin Wang, Jian Yang, Shengli Tang, Hao Liu, Jiaming Fan, Fugui Zhang, Evan M Farina, Maryam K Mohammed, Yulong Zou, Dongzhe Song, Junyi Liao, Jiayi Huang, Dan Guo, Minpeng Lu, Feng Liu, Jianxiang Liu, Li Li, Chao Ma, Xue Hu, Rex C Haydon, Michael J Lee, Russell R Reid, Guillermo A Ameer, Li Yang, Tong-Chuan He
Successful bone tissue engineering requires at the minimum sufficient osteoblast progenitors, efficient osteoinductive factors, and biocompatible scaffolding materials. We previously demonstrated that bone morphogenetic protein 9 (BMP9) is one of the most potent factors in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential use of a biodegradable citrate-based thermosensitive macromolecule, poly(polyethyleneglycol citrate-co-N-isopropylacrylamide) (PPCN) mixed with gelatin (PPCNG) as a scaffold for the delivery of BMP9-stimulated MSCs to promote localized bone formation...
April 2016: Biomedical Materials
Chang-Jun Pi, Kai-Lu Liang, Zhen-Yong Ke, Fu Chen, Yun Cheng, Liang-Jun Yin, Zhong-Liang Deng, Bai-Cheng He, Liang Chen
Mesenchymal stem cells (MSCs) are suitable seed cells for bone tissue engineering because they can self-renew and undergo differentiation into osteogenic, adipogenic, chondrogenic, or myogenic lineages. Vascular endothelial growth factor-a (VEGF-a), an angiogenic factor, is also involved in osteogenesis and bone repair. However, the effects of VEGF-a on osteogenic MSCs differentiation remain unknown. It was previously reported that bone morphogenetic protein9 (BMP9) is one of the most important osteogenic BMPs...
August 1, 2016: Biological Chemistry
Masako Fujioka-Kobayashi, Kosaku Sawada, Eizaburo Kobayashi, Benoit Schaller, Yufeng Zhang, Richard J Miron
OBJECTIVES: Combination therapies of growth factors and scaffolds for bone tissue engineering are becoming routine for clinical use. BMP9 has previously been characterized as one of the most osteogenic inducers among the BMP superfamily; however, up until recently, BMP9 has only been available through adenovirus transfection experiments (gene therapy). While recombinant human (rh)BMP2 is regarded as the gold standard for bone regeneration with recombinant growth factors, recently the successful development of rhBMP9 brings intriguing new possibilities for future clinical use...
March 14, 2016: Clinical Oral Implants Research
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