scholarly journals N-linked glycosylation of the antagonist Short gastrulation increases the functional complexity of BMP signals

2018 ◽  
Author(s):  
E. Negreiros ◽  
S. Herszterg ◽  
K. Hwa ◽  
A. Câmara ◽  
W.B. Dias ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Protein Complexes ◽  
Extracellular Milieu ◽  
Morphogenetic Protein ◽  
Glycosylation Sites ◽  
Evolutionarily Conserved ◽  
Bmp Pathway ◽  
Summary Statement ◽  
Bmp Antagonist

AbstractDisorders of N-linked glycosylation are increasingly reported in the literature. However, targets responsible for the associated developmental and physiological defects are largely unknown. Bone Morphogenetic Proteins (BMPs) act as highly dynamic complexes to regulate several functions during development. The range and strength of BMP activity depend on interactions with glycosylated protein complexes in the extracellular milieu. Here we investigate the role of glycosylation for the function of the conserved extracellular BMP antagonist Short gastrulation (Sog). We identify conserved N-glycosylated sites and describe the effect of mutating these residues on BMP pathway activity in Drosophila. Functional analysis reveals that loss of individual Sog glycosylation sites enhances BMP antagonism and/or increases the spatial range of Sog effects in the tissue. Mechanistically, we provide evidence that N-terminal and stem glycosylation controls extracellular Sog levels and distribution. The identification of similar residues in vertebrate Chordin proteins suggests that N-glycosylation may be an evolutionarily conserved process that adds complexity to the regulation of BMP activity.Summary StatementN-glycosylation restricts the function of Short gastrulation during Drosophila development by controlling the amount of extracellular protein. This adds another layer of complexity to regulation of Bone Morphogenetic Protein signals.

scholarly journals The BMP signaling pathway is required together with the FGF pathway for notochord induction in the ascidian embryo

Development ◽  
2001 ◽  
Vol 128 (14) ◽  
pp. 2629-2638 ◽  
Author(s):  
Sébastien Darras ◽  
Hiroki Nishida
Keyword(s):  
Time Window ◽  
Bmp Signaling ◽  
Cell Stage ◽  
Morphogenetic Protein ◽  
Positive Target ◽  
Bmp Pathway ◽  
Notochord Cells ◽  
Bmp Antagonist ◽  
Ascidian Embryo

The 40 notochord cells of the ascidian tadpole invariably arise from two different lineages: the primary (A-line) and the secondary (B-line) lineages. It has been shown that the primary notochord cells are induced by presumptive endoderm blastomeres between the 24-cell and the 64-cell stage. Signaling through the fibroblast growth factor (FGF) pathway is required for this induction. We have investigated the role of the bone morphogenetic protein (BMP) pathway in ascidian notochord formation. HrBMPb (the ascidian BMP2/4 homologue) is expressed in the anterior endoderm at the 44-cell stage before the completion of notochord induction. The BMP antagonist Hrchordin is expressed in a complementary manner in all surrounding blastomeres and appears to be a positive target of the BMP pathway. Unexpectedly, chordin overexpression reduced formation of both primary and secondary notochord. Conversely, primary notochord precursors isolated prior to induction formed notochord in presence of BMP-4 protein. While bFGF protein had a similar activity, notochord precursors showed a different time window of competence to respond to BMP-4 and bFGF. Our data are consistent with bFGF acting from the 24-cell stage, while BMP-4 acts during the 44-cell stage. However, active FGF signaling was also required for induction by BMP-4. In the secondary lineage, notochord specification also required two inducing signals: an FGF signal from anterior and posterior endoderm from the 24-cell stage and a BMP signal from anterior endoderm during the 44-cell stage.

scholarly journals The Role of BMP Signaling in Osteoclast Regulation

2021 ◽  
Vol 9 (3) ◽  
pp. 24
Author(s):  
Brian Heubel ◽  
Anja Nohe
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Proteins ◽  
Bone Diseases ◽  
Bmp Signaling ◽  
Bone Homeostasis ◽  
Direct Stimulation ◽  
Federal Drug Administration ◽  
Bmp Pathway ◽  
Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

Suppression of GATA factor activity causes axis duplication in Xenopus

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4595-4605 ◽  
Author(s):  
T.G. Sykes ◽  
A.R. Rodaway ◽  
M.E. Walmsley ◽  
R.K. Patient
Keyword(s):  
Cell Fate ◽  
Homeobox Gene ◽  
Dominant Negative ◽  
Gata Factor ◽  
Dorsoventral Axis ◽  
Morphogenetic Protein ◽  
Head Formation ◽  
Bmp Signalling ◽  
Bmp Antagonist

In Xenopus, the dorsoventral axis is patterned by the interplay between active signalling in ventral territories, and secreted antagonists from Spemann's organiser. Two signals are important in ventral cells, bone morphogenetic protein-4 (BMP-4) and Wnt-8. BMP-4 plays a conserved role in patterning the vertebrate dorsoventral axis, whilst the precise role of Wnt-8 and its relationship with BMP-4, are still unclear. Here we have investigated the role played by the GATA family of transcription factors, which are expressed in ventral mesendoderm during gastrulation and are required for the differentiation of blood and endodermal tissues. Injection ventrally of a dominant-interfering GATA factor (called G2en) induced the formation of secondary axes that phenocopy those induced by the dominant-negative BMP receptor. However, unlike inhibiting BMP signalling, inhibiting GATA activity in the ectoderm does not lead to neuralisation. In addition, analysis of gene expression in G2en injected embryos reveals that at least one known target gene for BMP-4, the homeobox gene Vent-2, is unaffected. In contrast, the expression of Wnt-8 and the homeobox gene Vent-1 is suppressed by G2en, whilst the organiser-secreted BMP antagonist chordin becomes ectopically expressed. These data therefore suggest that GATA activity is essential for ventral cell fate and that subsets of ventralising and dorsalising genes require GATA activity for their expression and suppression, respectively. Finally, using G2en, we show that suppression of Wnt-8 expression, in conjunction with blocked BMP signalling, does not lead to head formation, suggesting that the head-suppressing Wnt signal may not be Wnt-8.

Key role of the expression of bone morphogenetic proteins in increasing the osteogenic activity of osteoblast-like cells exposed to shock waves and seeded on bioactive glass-ceramic scaffolds for bone tissue engineering

2014 ◽  
Vol 29 (5) ◽  
pp. 728-736 ◽  
Author(s):  
Giuliana Muzio ◽  
Germana Martinasso ◽  
Francesco Baino ◽  
Roberto Frairia ◽  
Chiara Vitale-Brovarone ◽  
...  
Keyword(s):  
Shock Wave ◽  
Alkaline Phosphatase ◽  
Shock Waves ◽  
Bioactive Glass ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Proteins ◽  
Glass Ceramic ◽  
Osteogenic Activity ◽  
Morphogenetic Protein

In this work, the role of shock wave-induced increase of bone morphogenetic proteins in modulating the osteogenic properties of osteoblast-like cells seeded on a bioactive scaffold was investigated using gremlin as a bone morphogenetic protein antagonist. Bone-like glass-ceramic scaffolds, based on a silicate experimental bioactive glass developed at the Politecnico di Torino, were produced by the sponge replication method and used as porous substrates for cell culture. Human MG-63 cells, exposed to shock waves and seeded on the scaffolds, were treated with gremlin every two days and analysed after 20 days for the expression of osteoblast differentiation markers. Shock waves have been shown to induce osteogenic activity mediated by increased expression of alkaline phosphatase, osteocalcin, type I collagen, BMP-4 and BMP-7. Cells exposed to shock waves plus gremlin showed increased growth in comparison with cells treated with shock waves alone and, conversely, mRNA contents of alkaline phosphatase and osteocalcin were significantly lower. Therefore, the shock wave-mediated increased expression of bone morphogenetic protein in MG-63 cells seeded on the scaffolds is essential in improving osteogenic activity; blocking bone morphogenetic protein via gremlin completely prevents the increase of alkaline phosphatase and osteocalcin. The results confirmed that the combination of glass-ceramic scaffolds and shock waves exposure could be used to significantly improve osteogenesis opening new perspectives for bone regenerative medicine.

scholarly journals A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Jonathan W. Lowery ◽  
Brice Brookshire ◽  
Vicki Rosen
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Bmp Signaling ◽  
Protein Signaling ◽  
Bone Morphogenetic Protein Signaling ◽  
Human Organ ◽  
Morphogenetic Protein ◽  
Organ Systems ◽  
Bmp Pathway ◽  
Wide Perspective ◽  
The Relationship

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-βfamily of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-βpathways.

Heparin/heparan sulphate binding in the TGF-β cytokine superfamily

2006 ◽  
Vol 34 (3) ◽  
pp. 458-460 ◽  
Author(s):  
C.C. Rider
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Transforming Growth Factor ◽  
Heparan Sulphate ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Binding Properties ◽  
And Migration ◽  
Close Relatives ◽  
Bmp Antagonist

The TGF-β (transforming growth factor-β) cytokine superfamily in mammals contains some 30 members. These dimeric proteins are characterized by a strongly conserved cystine knot-based structure. They regulate the proliferation, differentiation and migration of many cell types, and therefore have important roles in morphogenesis, organogenesis, tissue maintenance and wound healing. Thus far, around one-quarter of these cytokines have been shown to bind to heparin and heparan sulphate. Well-established examples are the TGF-β isoforms 1 and 2, and the BMPs (bone morphogenetic proteins) -2 and -4. In studies in my laboratory, we have shown that GDNF (glial-cell-line-derived neurotrophic factor) and its close relatives neurturin and artemin bind to heparin and heparan sulphate with high affinity. We have reported previously that binding of GDNF is highly dependent on the presence of 2-O-sulphate groups. More recently, we and others have been investigating the heparin/heparan sulphate-binding properties of BMP-7, which is a representative of a distinct BMP subgroup from that of BMPs -2 and -4. Interestingly, several of the various specific BMP antagonist proteins also bind to heparin and heparan sulphate. Much remains to be learnt about the nature and role of glycosaminoglycan interactions in the TGF-β superfamily, but current work suggests that these cytokines do not share a single highly conserved heparin/heparan sulphate-binding site.

scholarly journals Inhibition of the BMP pathway prevents development of Barrett’s-associated adenocarcinoma in a surgical rat model

2021 ◽  
Author(s):  
Wytske M Westra ◽  
Danielle Straub ◽  
Francesca Milano ◽  
Navtej S Buttar ◽  
Kenneth K Wang ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Reflux Esophagitis ◽  
Rat Model ◽  
Controlled Trial ◽  
Local Delivery ◽  
Chi Square ◽  
Randomized Controlled ◽  
Aggressive Cancer ◽  
Bmp Pathway ◽  
Bmp Antagonist

Summary Introduction Esophageal adenocarcinoma (EAC) is an aggressive cancer, associated with reflux esophagitis and intestinal metaplasia (IM). One underlying biological mechanism, which possibly drives the development of EAC, is the dysregulated expression of Bone Morphogenetic Proteins (BMPs). Aim To investigate if local delivery of Noggin, a BMP antagonist, reduced EAC. Methods After obtaining proof of principal on local delivery of a Noggin/Sucralfate substance, a randomized controlled trial to test the effects of Noggin on EAC development was performed in a surgical rat model. In the model, an esophago-jejunostomy leads to development of reflux-esophagitis, IM and eventually EAC. Rats were treated by Noggin/Sucralfate or Sucralfate alone. Treatment was administered from 26 to 29 weeks after the operation. Results Of the 112 operated rats, 52 survived beyond 26 weeks. Finally, 25 rats treated with Noggin/Sucralfate and 21 with Sucralfate, were evaluated. At the end, 39 (85%) of the animals had IM while 28 (61%) developed cancer. There were significantly more cancers in the Noggin/Sucralfate arm (50%) versus the Sucralfate group (73%) (Chi square, P < 0.05). Most cancers were mucous producing T3 adenocarcinomas. There were no significant differences in the amount of IM, size or grade of the cancers, or expression of columnar and squamous markers between the two groups. Conclusion In this study, we demonstrated that inhibition of BMPs by Noggin reduced development of EAC in a surgical esophagitis-IM-EAC rat model. In future, effective targeting of the BMP pathway with selective BMP-inhibitors could become an important asset to improve EAC patient outcome.

scholarly journals In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2

Blood ◽  
2010 ◽  
Vol 116 (18) ◽  
pp. 3635-3644 ◽  
Author(s):  
Ken Maes ◽  
Elizabeta Nemeth ◽  
G. David Roodman ◽  
Alissa Huston ◽  
Flavia Esteve ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Morphogenetic Proteins ◽  
Bone Morphogenetic Protein 2 ◽  
Minor Effect ◽  
Morphogenetic Protein ◽  
Huh7 Cells ◽  
Serum Hepcidin ◽  
Stimulatory Capacity ◽  
A Minor

Abstract Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6–responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti–BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti–IL-6 blocked it with a minority of sera, whereas anti–BMP-4, -6, or -9 antibodies had no effect. BMP-2–immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera.

scholarly journals Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5021-5029 ◽  
Author(s):  
Antonella Nai ◽  
Alessia Pagani ◽  
Giacomo Mandelli ◽  
Maria Rosa Lidonnici ◽  
Laura Silvestri ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Absorption ◽  
Therapeutic Option ◽  
Iron Loading ◽  
Proof Of Concept ◽  
Ineffective Erythropoiesis ◽  
Morphogenetic Protein ◽  
Bmp Pathway ◽  
Partial Correction

Abstract Inappropriately low expression of the key iron regulator hepcidin (HAMP) causes iron overload in untransfused patients affected by β-thalassemia intermedia and Hamp modulation provides improvement of the thalassemic phenotype of the Hbbth3/+ mouse. HAMP expression is activated by iron through the bone morphogenetic protein (BMP)–son of mothers against decapentaplegic signaling pathway and inhibited by ineffective erythropoiesis through an unknown “erythroid regulator.” The BMP pathway is inactivated by the serine protease TMPRSS6 that cleaves the BMP coreceptor hemojuvelin. Here, we show that homozygous loss of Tmprss6 in Hbbth3/+ mice improves anemia and reduces ineffective erythropoiesis, splenomegaly, and iron loading. All these effects are mediated by Hamp up-regulation, which inhibits iron absorption and recycling. Because Hbbth3/+ mice lacking Tmprss6 show residual ineffective erythropoiesis, our results indicate that Tmprss6 is essential for Hamp inhibition by the erythroid regulator. We also obtained partial correction of the phenotype in Tmprss6 haploinsufficient Hbbth3/+ male but not female mice and showed that the observed sex difference reflects an unequal balance between iron and erythropoiesis-mediated Hamp regulation. Our study indicates that preventing iron overload improves β-thalassemia and strengthens the essential role of Tmprss6 for Hamp suppression, providing a proof of concept that Tmprss6 manipulation can offer a novel therapeutic option in this condition.

scholarly journals Protein associated with SMAD1 (PAWS1/FAM83G) is a substrate for type I bone morphogenetic protein receptors and modulates bone morphogenetic protein signalling

Open Biology ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 130210 ◽  
Author(s):  
Janis Vogt ◽  
Kevin S. Dingwell ◽  
Lina Herhaus ◽  
Robert Gourlay ◽  
Thomas Macartney ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Proteins ◽  
Target Genes ◽  
Type I ◽  
Independent Manner ◽  
Bmp Receptor ◽  
Morphogenetic Protein ◽  
Receptor Kinases ◽  
Protein Receptors ◽  
Bmp Pathway

Bone morphogenetic proteins (BMPs) control multiple cellular processes in embryos and adult tissues. BMPs signal through the activation of type I BMP receptor kinases, which then phosphorylate SMADs 1/5/8. In the canonical pathway, this triggers the association of these SMADs with SMAD4 and their translocation to the nucleus, where they regulate gene expression. BMPs can also signal independently of SMAD4, but this pathway is poorly understood. Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS . Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. We also demonstrate that PAWS1 regulates the expression of several non-BMP target genes, suggesting roles for PAWS1 beyond the BMP pathway.

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