scholarly journals Fibrillin-1 and -2 differentially modulate endogenous TGF-β and BMP bioavailability during bone formation

2010 ◽  
Vol 190 (6) ◽  
pp. 1107-1121 ◽  
Author(s):  
Harikiran Nistala ◽  
Sui Lee-Arteaga ◽  
Silvia Smaldone ◽  
Gabriella Siciliano ◽  
Luca Carta ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transforming Growth Factor ◽  
Bone Mineralization ◽  
Bmp Signaling ◽  
Direct Role ◽  
Morphogenetic Protein ◽  
Fibrillin 1 ◽  
Osteoblast Maturation

Extracellular regulation of signaling by transforming growth factor (TGF)–β family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular microfibrils, differentially regulate TGF-β and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2–null (Fbn2−/−) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2−/− phenotype is accounted for by improper activation of latent TGF-β that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1−/− mice exhibit improper latent TGF-β activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of microfibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-β and BMP signaling.

scholarly journals The Bone Regeneration Capacity of BMP-2 + MMP-10 Loaded Scaffolds Depends on the Tissue Status

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 979
Author(s):  
Patricia Garcia-Garcia ◽  
Ricardo Reyes ◽  
José Antonio Rodriguez ◽  
Tomas Martín ◽  
Carmen Evora ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Regeneration ◽  
Growth Promotion ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Therapeutic Molecules ◽  
Positive Effect

Biomaterials-mediated bone formation in osteoporosis (OP) is challenging as it requires tissue growth promotion and adequate mineralization. Based on our previous findings, the development of scaffolds combining bone morphogenetic protein 2 (BMP-2) and matrix metalloproteinase 10 (MMP-10) shows promise for OP management. To test our hypothesis, scaffolds containing BMP-2 + MMP-10 at variable ratios or BMP-2 + Alendronate (ALD) were prepared. Systems were characterized and tested in vitro on healthy and OP mesenchymal stem cells and in vivo bone formation was studied on healthy and OP animals. Therapeutic molecules were efficiently encapsulated into PLGA microspheres and embedded into chitosan foams. The use of PLGA (poly(lactic-co-glycolic acid)) microspheres as therapeutic molecule reservoirs allowed them to achieve an in vitro and in vivo controlled release. A beneficial effect on the alkaline phosphatase activity of non-OP cells was observed for both combinations when compared with BMP-2 alone. This effect was not detected on OP cells where all treatments promoted a similar increase in ALP activity compared with control. The in vivo results indicated a positive effect of the BMP-2 + MMP-10 combination at both of the doses tested on tissue repair for OP mice while it had the opposite effect on non-OP animals. This fact can be explained by the scaffold’s slow-release rate and degradation that could be beneficial for delayed bone regeneration conditions but had the reverse effect on healthy animals. Therefore, the development of adequate scaffolds for bone regeneration requires consideration of the tissue catabolic/anabolic balance to obtain biomaterials with degradation/release behaviors suited for the existing tissue status.

scholarly journals Matrix Vesicles: Role in Bone Mineralization and Potential Use as Therapeutics

2021 ◽  
Vol 14 (4) ◽  
pp. 289
Author(s):  
Sana Ansari ◽  
Bregje W. M. de de Wildt ◽  
Michelle A. M. Vis ◽  
Carolina E. de de Korte ◽  
Keita Ito ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Regeneration ◽  
Bone Cells ◽  
Bone Mineralization ◽  
Recipient Cell ◽  
Organic Matrix ◽  
Matrix Vesicles ◽  
Matrix Mineralization

Bone is a complex organ maintained by three main cell types: osteoblasts, osteoclasts, and osteocytes. During bone formation, osteoblasts deposit a mineralized organic matrix. Evidence shows that bone cells release extracellular vesicles (EVs): nano-sized bilayer vesicles, which are involved in intercellular communication by delivering their cargoes through protein–ligand interactions or fusion to the plasma membrane of the recipient cell. Osteoblasts shed a subset of EVs known as matrix vesicles (MtVs), which contain phosphatases, calcium, and inorganic phosphate. These vesicles are believed to have a major role in matrix mineralization, and they feature bone-targeting and osteo-inductive properties. Understanding their contribution in bone formation and mineralization could help to target bone pathologies or bone regeneration using novel approaches such as stimulating MtV secretion in vivo, or the administration of in vitro or biomimetically produced MtVs. This review attempts to discuss the role of MtVs in biomineralization and their potential application for bone pathologies and bone regeneration.

scholarly journals SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

2015 ◽  
Vol 35 (12) ◽  
pp. 2165-2172 ◽  
Author(s):  
Jonathon Marks-Bluth ◽  
Anchit Khanna ◽  
Vashe Chandrakanthan ◽  
Julie Thoms ◽  
Thomas Bee ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Selective Advantage ◽  
Regulatory Elements ◽  
Bmp Signaling ◽  
Tissue Specific ◽  
Morphogenetic Protein ◽  
Smad Signaling Pathway ◽  
Endothelial Development

The bone morphogenetic protein (BMP)/SMAD signaling pathway is a critical regulator of angiogenic sprouting and is involved in vascular development in the embryo. SMAD1 and SMAD5, the core mediators of BMP signaling, are vital for this activity, yet little is known about their transcriptional regulation in endothelial cells. Here, we have integrated multispecies sequence conservation, tissue-specific chromatin,in vitroreporter assay, andin vivotransgenic data to identify and validateSmad1+63 and theSmad5promoter as tissue-specificcis-regulatory elements that are active in the developing endothelium. The activity of these elements in the endothelium was dependent on highly conserved ETS, GATA, and E-box motifs, and chromatin immunoprecipitation showed high levels of enrichment of FLI1, GATA2, and SCL at these sites in endothelial cell lines and E11 dorsal aortasin vivo. Knockdown of FLI1 and GATA2 but not SCL reduced the expression of SMAD1 and SMAD5 in endothelial cellsin vitro. In contrast, CD31+cKit−endothelial cells harvested from embryonic day 9 (E9) aorta-gonad-mesonephros (AGM) regions of GATA2 null embryos showed reducedSmad1but notSmad5transcript levels. This is suggestive of a degree ofin vivoselection where, in the case of reduced SMAD1 levels, endothelial cells with more robust SMAD5 expression have a selective advantage.

ONO-1301 Enhances in vitro Osteoblast Differentiation and in vivo Bone Formation Induced by Bone Morphogenetic Protein

Spine ◽  
2018 ◽  
Vol 43 (11) ◽  
pp. E616-E624 ◽  
Author(s):  
Sadaaki Kanayama ◽  
Takashi Kaito ◽  
Kazuma Kitaguchi ◽  
Hiroyuki Ishiguro ◽  
Kunihiko Hashimoto ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Morphogenetic Protein ◽  
Osteoblast Differentiation ◽  
Morphogenetic Protein ◽  
In Vivo Bone Formation

scholarly journals BMP1 controls TGFβ1 activation via cleavage of latent TGFβ-binding protein

2006 ◽  
Vol 175 (1) ◽  
pp. 111-120 ◽  
Author(s):  
Gaoxiang Ge ◽  
Daniel S. Greenspan
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Matrix Metalloproteinase 2 ◽  
Potent Inducer ◽  
Mouse Embryo Fibroblasts ◽  
Morphogenetic Protein ◽  
Important Regulator ◽  
Vertebrate Tissue

Transforming growth factor β1 (TGFβ1), an important regulator of cell behavior, is secreted as a large latent complex (LLC) in which it is bound to its cleaved prodomain (latency-associated peptide [LAP]) and, via LAP, to latent TGFβ-binding proteins (LTBPs). The latter target LLCs to the extracellular matrix (ECM). Bone morphogenetic protein 1 (BMP1)–like metalloproteinases play key roles in ECM formation, by converting precursors into mature functional proteins, and in morphogenetic patterning, by cleaving the antagonist Chordin to activate BMP2/4. We provide in vitro and in vivo evidence that BMP1 cleaves LTBP1 at two specific sites, thus liberating LLC from ECM and resulting in consequent activation of TGFβ1 via cleavage of LAP by non–BMP1-like proteinases. In mouse embryo fibroblasts, LAP cleavage is shown to be predominantly matrix metalloproteinase 2 dependent. TGFβ1 is a potent inducer of ECM formation and of BMP1 expression. Thus, a role for BMP1-like proteinases in TGFβ1 activation completes a novel fast-forward loop in vertebrate tissue remodeling.

SMAD7 controls iron metabolism as a potent inhibitor of hepcidin expression

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2657-2665 ◽  
Author(s):  
Katarzyna Mleczko-Sanecka ◽  
Guillem Casanovas ◽  
Anan Ragab ◽  
Katja Breitkopf ◽  
Alexandra Müller ◽  
...  
Keyword(s):  
Growth Factor ◽  
Iron Metabolism ◽  
Negative Feedback ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Hepcidin Expression ◽  
Morphogenetic Protein ◽  
Smad Protein

Abstract Hepcidin is the master regulatory hormone of systemic iron metabolism. Hepcidin deficiency causes common iron overload syndromes whereas its overexpression is responsible for microcytic anemias. Hepcidin transcription is activated by the bone morphogenetic protein (BMP) and the inflammatory JAK-STAT pathways, whereas comparatively little is known about how hepcidin expression is inhibited. By using high-throughput siRNA screening we identified SMAD7 as a potent hepcidin suppressor. SMAD7 is an inhibitory SMAD protein that mediates a negative feedback loop to both transforming growth factor-β and BMP signaling and that recently was shown to be coregulated with hepcidin via SMAD4 in response to altered iron availability in vivo. We show that SMAD7 is coregulated with hepcidin by BMPs in primary murine hepatocytes and that SMAD7 overexpression completely abolishes hepcidin activation by BMPs and transforming growth factor-β. We identify a distinct SMAD regulatory motif (GTCAAGAC) within the hepcidin promoter involved in SMAD7-dependent hepcidin suppression, demonstrating that SMAD7 does not simply antagonize the previously reported hemojuvelin/BMP-responsive elements. This work identifies a potent inhibitory factor for hepcidin expression and uncovers a negative feedback pathway for hepcidin regulation, providing insight into a mechanism how hepcidin expression may be limited to avoid iron deficiency.

scholarly journals Reovirus Activates Transforming Growth Factor β and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection

2009 ◽  
Vol 83 (10) ◽  
pp. 5035-5045 ◽  
Author(s):  
J. David Beckham ◽  
Kathryn Tuttle ◽  
Kenneth L. Tyler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Downstream Signaling ◽  
Morphogenetic Protein ◽  
The Central Nervous System

ABSTRACT Viral infections of the central nervous system (CNS) are important causes of worldwide morbidity and mortality, and understanding how viruses perturb host cell signaling pathways will facilitate identification of novel antiviral therapies. We now show that reovirus infection activates transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling in a murine model of encephalitis in vivo. TGF-β receptor I (TGF-βRI) expression is increased and its downstream signaling factor, SMAD3, is activated in the brains of reovirus-infected mice. TGF-β signaling is neuroprotective, as inhibition with a TGF-βRI inhibitor increases death of infected neurons. Similarly, BMP receptor I expression is increased and its downstream signaling factor, SMAD1, is activated in reovirus-infected neurons in the brains of infected mice in vivo. Activated SMAD1 and SMAD3 were both detected in regions of brain infected by reovirus, but activated SMAD1 was found predominantly in uninfected neurons in close proximity to infected neurons. Treatment of reovirus-infected primary mouse cortical neurons with a BMP agonist reduced apoptosis. These data provide the first evidence for the activation of TGF-β and BMP signaling pathways following neurotropic viral infection and suggest that these signaling pathways normally function as part of the host's protective innate immune response against CNS viral infection.

scholarly journals CHIP Mediates Degradation of Smad Proteins and Potentially Regulates Smad-Induced Transcription

2004 ◽  
Vol 24 (2) ◽  
pp. 856-864 ◽  
Author(s):  
Linyu Li ◽  
Hong Xin ◽  
Xialian Xu ◽  
Mei Huang ◽  
Xinjun Zhang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Transforming Growth Factor Beta ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Interacting Protein ◽  
Receptor Complexes ◽  
Morphogenetic Protein ◽  
Smad Proteins

ABSTRACT Transforming growth factor beta (TGF-β)/bone morphogenetic protein (BMP) family ligands interact with specific membrane receptor complexes that have serine/threonine kinase activities. The receptor phosphorylation and activation induced by the ligands leads to phosphorylation of the Smad proteins, which translocate to the nucleus, controlling gene expression. Thus, regulation of Smad proteins is a key step in TGF-β/BMP-induced signal transduction. Here we report a novel mechanism of the regulation of SMAD-mediated signaling, by which the Smad1 protein level is controlled through expression of the CHIP protein. CHIP is a U-box-dependent E3 ubiquitin ligase, previously identified as a cochaperon protein. However, we have isolated CHIP as a Smad-interacting protein in a yeast two-hybrid screen using Smad1 as bait. Furthermore we have shown CHIP-Smad interaction using the 35S-labeled CHIP protein, which can interact with glutathione S-transferase (GST)-Smad1 and GST-Smad4 in an in vitro protein-binding assay. The CHIP-Smad interaction has been confirmed in vivo in mammalian cells through coimmunoprecipitation. Interestingly, we demonstrate that the coexpression of Smad1 and Smad4 with the CHIP protein results in the degradation of the Smad proteins through a ubiquitin-mediated process. Consistent with the observation that CHIP induces Smad1 degradation, we further show that the expression of CHIP can inhibit the transcriptional activities of the Smad1/Smad4 complex induced by BMP signals. Intriguingly, pBS/U6/CHIPi, which diminishes CHIP expression, significantly enhanced Smad1/Smad4- or BMPRIB(QD)-induced gene transcription. These results suggest that CHIP can interact with the Smad1/Smad4 proteins and block BMP signal transduction through the ubiquitin-mediated degradation of Smad proteins.

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