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Bone Morphogenic Protein (bone + morphogenic_protein)
Selected AbstractsBone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2008Kim Loh Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways. © 2008 Wiley-Liss, Inc. [source] rhBMP-2, rhVEGF165, rhPTN and thrombin-related peptide, TP508 induce chemotaxis of human osteoblasts and microvascular endothelial cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 3 2005Gang Li Abstract Osteogenesis and angiogenesis are inter-linked and tightly regulated processes involved in growth, repair, and bone remodeling. Bone morphogenic protein 2 (BMP-2), vascular endothelial growth factor (VEGF), pleiotrophin (PTN) and thrombin-related peptide, TP508 have all been found to have the ability to promote bone fracture healing by enhancing both the osteogenesis and angiogenesis processes. One of the underlying mechanisms proposed is that mediators for osteogenesis may also be involved in mediating angiogenesis and vice versa. The aim of this study was to examine the chemotactic effects of rhBMP-2, rhVEGF165, rhPTN and TP508 on human osteoblasts and endothelial cells. Using a direct-viewing chemotaxis assay system, we report for the first time, the direct quantitative observation of chemotaxis of both human osteoblastc cells and microvascular endothelial cells towards sources of rhBMP-2, rhVEGF165, rhPTN and TP508. This study confirmed that rhBMP-2, rhVEGF165, rhPTN and TP508 have chemotactic effects on both human osteoblastic and endothelial cells, indicating that these factors are directly involved in promoting angiogenesis and osteogenesis by recruiting osteoblasts and endothelial cells via chemotaxis. © 2005 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. [source] Bone morphogenic protein 3 inactivation is an early and frequent event in colorectal cancer developmentGENES, CHROMOSOMES AND CANCER, Issue 6 2008Kim Loh Bone morphogenic proteins (BMPs) are members of the TGFB growth factor superfamily with well-described functions in bone formation. Although disrupted BMP signalling in tumor development has more recently been investigated, a role for BMP3 in colorectal cancer (CRC) has remained largely unexplored. The aim of this study was to investigate BMP3 disruption in CRCs in relation to both the traditional and serrated pathways of tumor progression. BMP3 was down-regulated as assessed by real-time PCR in 50 of 56 primary tumors (89%). Bisulfite sequencing of the putative promoter revealed extensive hypermethylation in the cell line HT29, in which expression could be restored by treatment with a methyltransferase inhibitor. Aberrant hypermethylation was observed in 33/60 (55%) tumors and was highly correlated with microsatellite instability (P < 0.01), the CpG Island Methylator Phenotype (P < 0.01), BRAF oncogene mutation (P < 0.01), and proximal location (P < 0.001). Methylation was also frequently observed in serrated and traditional adenomatous polyps (22/29, 76%). Re-introduction of BMP3 into cell lines revealed marked growth suppression supporting the functional relevance of this alteration in colorectal tumor development. This study provides molecular and functional data supporting the importance of BMP3 silencing as an early and frequent event in colorectal tumors progressing via the serrated and traditional pathways. © 2008 Wiley-Liss, Inc. [source] Bone morphogenetic proteins in vertebrate hematopoietic developmentJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2004Alexandra Snyder Abstract During embryonic development, the hematopoietic system is the first to generate terminally differentiated, functional cell types. The urgent necessity for the early formation of blood and blood vessels during embryogenesis means that the induction, expansion, and maturation of these systems must be rapidly and precisely controlled. Bone morphogenic proteins (BMPs) have been implicated in hematopoietic development in the vertebrate embryo and stimulate the proliferation and/or differentiation of human cord blood hematopoietic stem cells (HSC) and embryonic stem cells in vitro. Here we review the mechanisms of action and potential roles of these soluble signaling molecules in vertebrate hematopoiesis. © 2004 Wiley-Liss, Inc. [source] Initiation of limb regeneration: The critical steps for regenerative capacityDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 1 2008Hitoshi Yokoyama While urodele amphibians (newts and salamanders) can regenerate limbs as adults, other tetrapods (reptiles, birds and mammals) cannot and just undergo wound healing. In adult mammals such as mice and humans, the wound heals and a scar is formed after injury, while wound healing is completed without scarring in an embryonic mouse. Completion of regeneration and wound healing takes a long time in regenerative and non-regenerative limbs, respectively. However, it is the early steps that are critical for determining the extent of regenerative response after limb amputation, ranging from wound healing with scar formation, scar-free wound healing, hypomorphic limb regeneration to complete limb regeneration. In addition to the accumulation of information on gene expression during limb regeneration, functional analysis of signaling molecules has recently shown important roles of fibroblast growth factor (FGF), Wnt/,-catenin and bone morphogenic protein (BMP)/Msx signaling. Here, the routine steps of wound healing/limb regeneration and signaling molecules specifically involved in limb regeneration are summarized. Regeneration of embryonic mouse digit tips and anuran amphibian (Xenopus) limbs shows intermediate regenerative responses between the two extremes, those of adult mammals (least regenerative) and urodele amphibians (more regenerative), providing a range of models to study the various abilities of limbs to regenerate. [source] Opposing effects on TSC-22 expression by BMP and receptor tyrosine kinase signals in the developing feather tractDEVELOPMENTAL DYNAMICS, Issue 1 2002Cord E. Dohrmann Abstract TSC-22 (transforming growth factor-,,stimulated clone 22) belongs to a family of leucine zipper transcription factors that includes sequences from invertebrates and vertebrates. The single Drosophila family member, encoded by the bunched gene, serves to integrate opposing bone morphogenic protein (BMP) and epidermal growth factor (EGF) signals during oogenesis. Similarly, mammalian TSC-22 expression is regulated by several families of secreted signaling molecules in cultured cells. Here, we show that chick TSC-22 is dynamically expressed in the condensing feather bud, as well as in many tissues of the chick embryo. BMP-2/4, previously shown to inhibit bud development, repress TSC-22 expression during feather bud formation in vivo. Noggin, a BMP antagonist, promotes TSC-22 expression. EGF, TGF-,, and fibroblast growth factor all promote both feather bud development and TSC-22 expression; each can promote ectopic feather buds that are regularly spaced between existing feather buds. Thus, TSC-22 is a candidate to integrate small imbalances in receptor tyrosine kinase and BMP signaling during feather tract development to generate stable and reproducible morphogenetic responses. © 2001 Wiley-Liss, Inc. [source] Functional differentiation of a clone resembling embryonic cortical interneuron progenitorsDEVELOPMENTAL NEUROBIOLOGY, Issue 14 2008Hedong Li Abstract We have generated clones (L2.3 and RG3.6) of neural progenitors with radial glial properties from rat E14.5 cortex that differentiate into astrocytes, neurons, and oligodendrocytes. Here, we describe a different clone (L2.2) that gives rise exclusively to neurons, but not to glia. Neuronal differentiation of L2.2 cells was inhibited by bone morphogenic protein 2 (BMP2) and enhanced by Sonic Hedgehog (SHH) similar to cortical interneuron progenitors. Compared with L2.3, differentiating L2.2 cells expressed significantly higher levels of mRNAs for glutamate decarboxylases (GADs), DLX transcription factors, calretinin, calbindin, neuropeptide Y (NPY), and somatostatin. Increased levels of DLX-2, GADs, and calretinin proteins were confirmed upon differentiation. L2.2 cells differentiated into neurons that fired action potentials in vitro, and their electrophysiological differentiation was accelerated and more complete when cocultured with developing astroglial cells but not with conditioned medium from these cells. The combined results suggest that clone L2.2 resembles GABAergic interneuron progenitors in the developing forebrain. © 2008 Wiley Periodicals, Inc. Develop Neurobiol 2008 [source] Cover Picture: Biomineralized Polysaccharide Capsules for Encapsulation, Organization, and Delivery of Human Cell Types and Growth Factors (Adv. Funct.ADVANCED FUNCTIONAL MATERIALS, Issue 6 2005Mater. Abstract The cover shows biomineralized polysaccharide capsules with specifiable make-up, which can provide microenvironments for stabilization, growth, and differentiation of human cell types, as reported by Oreffo and co-workers on p.,917. The capsules are amenable to complexation with a range of bioactive molecules and cells, offering tremendous potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues. The construction of biomimetic microenvironments with specific chemical and physical cues for the organization and modulation of a variety of cell populations is of key importance in tissue engineering. We show that a range of human cell types, including promyoblasts, chondrocytes, adipocytes, adenovirally transduced osteoprogenitors, immunoselected mesenchymal stem cells, and the osteogenic factor, rhBMP-2 (BMP: bone morphogenic protein), can be successfully encapsulated within mineralized polysaccharide capsules without loss of function in vivo. By controlling the extent of mineralization within the alginate/chitosan shell membrane, degradation of the shell wall and release of cells or rhBMP-2 into the surrounding medium can be regulated. In addition, we describe for the first time the ability to generate bead-in-bead capsules consisting of spatially separated cell populations and temporally separated biomolecule release, entrapped within alginate/chitosan shells of variable thickness, mineralization, and stability. Such materials offer significant potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues. [source] Biomineralized Polysaccharide Capsules for Encapsulation, Organization, and Delivery of Human Cell Types and Growth Factors,ADVANCED FUNCTIONAL MATERIALS, Issue 6 2005W. Green Abstract The construction of biomimetic microenvironments with specific chemical and physical cues for the organization and modulation of a variety of cell populations is of key importance in tissue engineering. We show that a range of human cell types, including promyoblasts, chondrocytes, adipocytes, adenovirally transduced osteoprogenitors, immunoselected mesenchymal stem cells, and the osteogenic factor, rhBMP-2 (BMP: bone morphogenic protein), can be successfully encapsulated within mineralized polysaccharide capsules without loss of function in vivo. By controlling the extent of mineralization within the alginate/chitosan shell membrane, degradation of the shell wall and release of cells or rhBMP-2 into the surrounding medium can be regulated. In addition, we describe for the first time the ability to generate bead-in-bead capsules consisting of spatially separated cell populations and temporally separated biomolecule release, entrapped within alginate/chitosan shells of variable thickness, mineralization, and stability. Such materials offer significant potential as multifunctional scaffolds and delivery vehicles in tissue regeneration of hard and soft tissues. [source] Modulation of bone morphogenic protein signalling alters numbers of astrocytes and oligodendroglia in the subventricular zone during cuprizone-induced demyelinationJOURNAL OF NEUROCHEMISTRY, Issue 1 2010Holly S. Cate J. Neurochem. (2010) 115, 11,22. Abstract The adult subventricular zone (SVZ) is a potential source of precursor cells to replace neural cells lost during demyelination. To better understand the molecular events that regulate neural precursor cell responsiveness in this context we undertook a microarray and quantitative PCR based analysis of genes expressed within the SVZ during cuprizone-induced demyelination. We identified an up-regulation of the genes encoding bone morphogenic protein 4 (BMP4) and its receptors. Immunohistochemistry confirmed an increase in BMP4 protein levels and also showed an increase in phosphorylated SMAD 1/5/8, a key component of BMP4 signalling, during demyelination. In vitro analysis revealed that neural precursor cells isolated from demyelinated animals, as well as those treated with BMP4, produce more astrocytes. Similarly, there were increased numbers of astrocytes in vivo within the SVZ during demyelination. Intraventricular infusion of Noggin, an endogenous antagonist of BMP4, during cuprizone-induced demyelination reduced pSMAD1/5/8, decreased astrocyte numbers and increased oligodendrocyte numbers in the SVZ. Our results suggest that lineage commitment of SVZ neural precursor cells is altered during demyelination and that BMP signalling plays a role in this process. [source] Adult cerebrospinal fluid inhibits neurogenesis but facilitates gliogenesis from fetal rat neural stem cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2009Judith Buddensiek Abstract Neural stem cells (NSCs) are a promising source for cell replacement therapies for neurological diseases. Administration of NSCs into the cerebrospinal fluid (CSF) offers a nontraumatic transplantation method into the brain. However, cell survival and intraparenchymal migration of the transplants are limited. Furthermore, CSF was recently reported to be an important milieu for controlling stem cell processes in the brain. We studied the effects of adult human leptomeningeal CSF on the behavior of fetal rat NSCs. CSF increased survival of NSCs compared with standard culture media during stem cell maintenance and differentiation. The presence of CSF enhanced NSC differentiation, leading to a faster loss of self-renewal capacity and faster and stronger neurite outgrowth. Some of these effects (mainly cell survival, neurite brancing) were blocked by addition of the bone morphogenic protein (BMP) inhibitor noggin. After differentiation in CSF, significantly fewer MAP2ab+ neurons were found, but there were more GFAP+ astroglia compared with standard media. By RT-PCR analysis, we determined a decrease of mRNA of the NSC marker gene Nestin but an increase of Gfap mRNA during differentiation up to 72 hr in CSF compared with standard media. Our data demonstrate that adult human leptomeningeal CSF enhances cell survival of fetal rat NSCs during proliferation and differentiation. Furthermore, CSF provides a stimulus for gliogenesis but inhibits neurogenesis from fetal NSCs. Our data suggest that CSF contains factors such as BMPs regulating NSC behavior, and we hypothesize that fast differentiation of NSCs in CSF leads to a rapid loss of migration capacity of intrathecally transplanted NSCs. © 2009 Wiley-Liss, Inc. [source] Differential effects of BMP-2 and TGF-,1 on chondrogenic differentiation of adipose derived stem cellsCELL PROLIFERATION, Issue 6 2007A. T. Mehlhorn Objectives: This article addresses the interaction of transforming growth factor ,1 (TGF-,1) and bone morphogenic protein 2 (BMP-2) during osteo-chondrogenic differentiation of adipose-derived adult stem cells (ASC). TGF-,1 was expected to modulate the BMP-2-induced effects through transcriptional regulation of Dlx-5, Msx-2 and Runx-2. Materials and Methods: Encapsulated ASC were cultured for 14 days in medium containing TGF-,1 and/or BMP-2. mRNA expression of the extracellular matrix molecules col2a1, cartilage oligomeric matrix protein, col10a1, alkaline phosphatase (AP) and transcription factors Msx-2, Dlx-5 and Runx-2 was analysed. Release of glycosaminoglycans, collagen types II and X into the extracellular matrix was demonstrated. Results: BMP-2 and TGF-,1 induced a chondrogenic phenotype in ASC. Combined growth factor treatment had a synergistic effect on col10a1 and an additive effect on col2a1 mRNA expression. Synthesis of glycosaminoglycans was enhanced by combined growth factor treatment. Addition of TGF-,1 inhibited BMP-2 induced AP expression and activity and both proteins promoted chondrogenic maturation. Conclusions: Prevention of BMP-2-induced osteogenic transdifferentiation by TGF-,1 seemed not to be mediated by transcriptional regulation of Dlx-5. Due to these findings, simultaneous stimulation of ASC with BMP-2 and TGF-,1 seemed to be beneficial for complete differentiation of ASC into chondrocytes. [source] A molecular recognition paradigm: promiscuity associated with the ligand,receptor interactions of the activin members of the TGF-, superfamilyJOURNAL OF MOLECULAR RECOGNITION, Issue 5 2005Hooi Hong Keah Abstract The structure,function properties of the pleiotropic activins and their relationship to other members of the transforming growth factor-, superfamily of proteins are described. In order to highlight the molecular promiscuity of these growth factors, emphasis has been placed on molecular features associated with the recognition by activin A and the bone morphogenic proteins of the corresponding extracellular domains of the ActRI and ActRII receptors. The available evidence suggests that the homodimeric activin A in its various functional roles has the propensity to fulfill key tasks in the regulation of mammalian cell behaviour, through coordination of numerous transcriptional and translational processes. Because of these profound effects, under physiologically normal conditions, activin A levels are closely controlled by a variety of binding partners, such as follistatin-288 and follistatin-315, ,2 -macroglobulin and other proteins. Moreover, the subunits of other members of the activin subfamily, such as activin B or activin C, are able to form heterodimers with the activin A subunit, thus providing a further avenue to positively or negatively control the physiological concentrations of activin A that are available for interaction with specific receptors and induction of cell signaling events. Based on data from X-ray crystallographic studies and homology modeling experiments, the molecular architecture of the ternary receptor,activin ligand complexes has been dissected, permitting rationalization in structural terms of the pattern of interactions that are the hallmark of this protein family. Copyright © 2005 John Wiley & Sons, Ltd. [source] | ||||||||||