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Cells
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Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases
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Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (10 January 2022) | Viewed by 32498

Special Issue Editor

Prof. Dr. Blanca Herrera

E-Mail Website
Guest Editor
Faculty of Pharmacy, Department Biochemistry and Molecular Biology, Complutense University of Madrid, Health Research Institute of the Hospital Clínico San Carlos, Madrid, Spain
Interests: liver; signalling; TGF-beta; BMP9; hepatocellular carcinoma; chronic liver disease; HGF/Met; hepatic progenitor cell; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although BMPs were discovered through their ability to induce ectopic bone formation, a seminal finding by Marshall Urist in 1965. Today, they are known to be involved in such a wide variety of processes that it has been suggested to rename them to “Body’” Morphogenetic Proteins instead of “Bone” Morphogenetic Proteins.

BMP family members are involved in a wide-ranging and continuously expanding number of functions, including dorsal-ventral pattern formation, morphogenesis, organogenesis, cell differentiation, and lineage direction of stem cells. In adult organisms, BMPs also control several cellular processes, including cell proliferation, differentiation, apoptosis/survival, autophagy, chemotaxis, and migration/invasion in many different cell types, and they play critical roles in different organ systems.

BMP signaling is extensively regulated at different levels: extracellularly, by a plethora of receptors, co-receptors, and agonist and antagonist extracellular molecules; and intracellularly, where finely tuned Smad and non-Smad signaling pathways modulate downstream cellular responses.

Thus, dysregulation of BMP signaling has pathological consequences, and accumulating evidence points at BMPs as the epicenter of many human diseases. Furthermore, BMPs signaling is seen as a clinical target with therapeutic potential.

In this Special Issue, we would like to give the possibility to share new data of undiscovered BMP functions, new hints in the regulation of BMP signaling, and its possible crosstalk with other pathways, and new findings uncovering the BMP roles in human diseases. We invite experts to contribute with research papers and critical reviews on these subjects, aiming to contribute to a deeper understanding of BMP signaling on health and disease.

Prof. Dr. Blanca Herrera
Guest Editor

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Keywords

  • BMPs
  • Signaling
  • Smad pathway
  • Non-Smad signaling
  • Extracellular regulators
  • Development
  • Morphogens
  • Adult homeostasis
  • Metabolism
  • Disease
  • Therapy

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Published Papers (6 papers)

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Research

Jump to: Review

17 pages, 1929 KiB  
Article
BMP9 Promotes an Epithelial Phenotype and a Hepatocyte-like Gene Expression Profile in Adult Hepatic Progenitor Cells
by Annalisa Addante, Carlos González-Corralejo, Cesáreo Roncero, Nerea Lazcanoiturburu, Juan García-Sáez, Blanca Herrera and Aránzazu Sánchez
Cells 2022, 11(3), 365; https://doi.org/10.3390/cells11030365 - 21 Jan 2022
Cited by 4 | Viewed by 3280
Abstract
Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, has emerged as a new player in chronic liver diseases (CLDs). Its levels increase in the fibrotic liver where it promotes fibrogenesis. It also regulates hepatic progenitor cells (oval cells in rodents), [...] Read more.
Bone morphogenetic protein 9 (BMP9), a member of the TGF-β superfamily, has emerged as a new player in chronic liver diseases (CLDs). Its levels increase in the fibrotic liver where it promotes fibrogenesis. It also regulates hepatic progenitor cells (oval cells in rodents), a cell population that contributes to repopulate the liver and recover functionality upon severe damage, but it can also be pro-fibrogenic, depending upon the hepatic microenvironment. Here we analyze the effect of chronic exposure to BMP9 in oval cells. We show that cells chronically treated with BMP9 (B9T-OC) display a more epithelial and hepatocyte-like phenotype while acquiring proliferative and survival advantages. Since our previous studies had revealed a functional crosstalk between BMP9 and the HGF/c-Met signaling pathways in oval cells, we analyzed a possible role for HGF/c-Met in BMP9-induced long-term effects. Data evidence that active c-Met signaling is necessary to obtain maximum effects in terms of BMP9-triggered hepatocytic differentiation potential, further supporting functionally relevant cooperation between these pathways. In conclusion, our work reveals a novel action of BMP9 in liver cells and helps elucidate the mechanisms that serve to increase oval cell regenerative potential, which could be therapeutically modulated in CLD. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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24 pages, 3623 KiB  
Article
Bmp Signal Gradient Modulates Convergent Cell Movement via Xarhgef3.2 during Gastrulation of Xenopus Embryos
by Jaeho Yoon, Vijay Kumar, Ravi Shankar Goutam, Sung-Chan Kim, Soochul Park, Unjoo Lee and Jaebong Kim
Cells 2022, 11(1), 44; https://doi.org/10.3390/cells11010044 - 24 Dec 2021
Cited by 3 | Viewed by 3924
Abstract
Gastrulation is a critical step in the establishment of a basic body plan during development. Convergence and extension (CE) cell movements organize germ layers during gastrulation. Noncanonical Wnt signaling has been known as major signaling that regulates CE cell movement by activating Rho [...] Read more.
Gastrulation is a critical step in the establishment of a basic body plan during development. Convergence and extension (CE) cell movements organize germ layers during gastrulation. Noncanonical Wnt signaling has been known as major signaling that regulates CE cell movement by activating Rho and Rac. In addition, Bmp molecules are expressed in the ventral side of a developing embryo, and the ventral mesoderm region undergoes minimal CE cell movement while the dorsal mesoderm undergoes dynamic cell movements. This suggests that Bmp signal gradient may affect CE cell movement. To investigate whether Bmp signaling negatively regulates CE cell movements, we performed microarray-based screening and found that the transcription of Xenopus Arhgef3.2 (Rho guanine nucleotide exchange factor) was negatively regulated by Bmp signaling. We also showed that overexpression or knockdown of Xarhgef3.2 caused gastrulation defects. Interestingly, Xarhgef3.2 controlled gastrulation cell movements through interacting with Disheveled (Dsh2) and Dsh2-associated activator of morphogenesis 1 (Daam1). Our results suggest that Bmp gradient affects gastrulation cell movement (CE) via negative regulation of Xarhgef3.2 expression. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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16 pages, 2530 KiB  
Article
Platelet Bone Morphogenetic Protein-4 Mediates Vascular Inflammation and Neointima Formation after Arterial Injury
by Marietta Jank, Nikolaus von Niessen, Christoph B. Olivier, Hannah Schmitt, Nathaly Anto-Michel, Ingo Hilgendorf, Christoph Bode, Martin Moser, Jennifer S. Esser and Qian Zhou
Cells 2021, 10(8), 2027; https://doi.org/10.3390/cells10082027 - 8 Aug 2021
Cited by 13 | Viewed by 3133
Abstract
The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (BMP4Plt−/−) were generated. [...] Read more.
The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (BMP4Plt−/−) were generated. Intravital microscopy was performed to evaluate leukocyte adhesion to the vessel wall. Expression of adhesion molecules and chemokines were analyzed. Platelet-leukocyte aggregates (PLAs) were evaluated using flow cytometry. For carotid wire injury, BMP4Plt−/− mice were further crossed with LDLr−/− mice (BMP4Plt−/−/LDLr−/−) and fed with a high cholesterol diet for 2-weeks. Carotid wire injury was performed, and re-endothelialization and neointimal formation were evaluated. In comparison to the control mice, stimulation with TNFα resulted in fewer rolling and adherent leukocytes to the vessel wall in the BMP4Plt−/− mice. mRNA and protein expression of P-selectin and adhesion molecules were reduced in the aorta of the BMP4Plt−/− mice. In platelets from the BMP4Plt−/− mice, the expression of P-selectin was reduced, and fewer PLA formations were measured than in the control mice. Loss of platelet BMP-4 further prevented neointima formation after carotid wire injury. Endothelial regeneration after injury was decelerated in the BMP4Plt−/− mice, and confirmed in-vitro, where the deletion of platelet BMP-4 inhibited endothelial cell proliferation and migration. We demonstrate for the first time that platelet BMP-4 is involved during vascular inflammation and remodeling. This is partially mediated by the inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory responses. Our findings identify platelet BMP-4 as a mediator of vascular inflammation in early atherosclerosis and restenosis. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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11 pages, 834 KiB  
Article
Serum Levels of Bone Morphogenetic Proteins 2 and 4 in Patients with Acute Myocardial Infarction
by Maria Kercheva, Anna M. Gusakova, Tamara R. Ryabova, Tatiana E. Suslova, Julia Kzhyshkowska and Vyacheslav V. Ryabov
Cells 2020, 9(10), 2179; https://doi.org/10.3390/cells9102179 - 27 Sep 2020
Cited by 15 | Viewed by 3421
Abstract
Background: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics. Methods: We studied the dynamics of serum levels of BMPs, its [...] Read more.
Background: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics. Methods: We studied the dynamics of serum levels of BMPs, its correlation with markers of LVR and with parameters of echocardiography in patients (n = 31) during the six-month follow-up period after myocardial infarction (MI). Results: Elevated serum levels of BMPs decreased by the six-month follow-up period. BMP-2 decreased from the first day after MI, and BMP-4 decreased from the Day 14. The elevated level of BMP-2 at Day 1 was associated with a lower level of troponin I, reperfusion time and better left ventricular ejection fraction (LV EF) at the six-month follow-up. Elevated serum level of BMP-4 at Day 1 was associated with a lower level of a soluble isoform of suppression of tumorigenicity 2 (sST2), age and reperfusion time. An elevated level of BMP-2 at the six-month follow-up was associated with higher levels of BMP-4, high-sensitivity C-reactive protein (hCRP) and sST2. High serum level of BMP-2 correlated with high levels of hCRP and matrix metalloproteinase (MMP)-9 on Day 7. High serum level of BMP-4 correlated with low levels of hCRP, MMP-9 at Day 3, sST2 at Day 1 and with decreased LV EF on Day 7. The findings of multivariate analysis support the involvement of BMP-2 in the development of post-infarction LVR. Conclusions: Our research translates experimental data about the BMPs in the development of adverse LVR into the clinic. Elevated serum levels of BMPs decreased by the end of the six-month period after MI. BMP-2 decreased from the first day and BMP-4 decreased from Day 14. BMP-2 and BMP-4 were associated with the development of LVR. Their correlations with markers of inflammation, degradation of the extracellular matrix, hemodynamic stress and markers of myocardial damage further support our hypothesis. Diagnostic and predictive values of these BMPs at the development of post-infarction LVR in vivo should be investigated further. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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Review

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47 pages, 7312 KiB  
Review
BMP Signaling Pathway in Dentin Development and Diseases
by Mengmeng Liu, Graham Goldman, Mary MacDougall and Shuo Chen
Cells 2022, 11(14), 2216; https://doi.org/10.3390/cells11142216 - 16 Jul 2022
Cited by 43 | Viewed by 10812
Abstract
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction [...] Read more.
BMP signaling plays an important role in dentin development. BMPs and antagonists regulate odontoblast differentiation and downstream gene expression via canonical Smad and non-canonical Smad signaling pathways. The interaction of BMPs with their receptors leads to the formation of complexes and the transduction of signals to the canonical Smad signaling pathway (for example, BMP ligands, receptors, and Smads) and the non-canonical Smad signaling pathway (for example, MAPKs, p38, Erk, JNK, and PI3K/Akt) to regulate dental mesenchymal stem cell/progenitor proliferation and differentiation during dentin development and homeostasis. Both the canonical Smad and non-canonical Smad signaling pathways converge at transcription factors, such as Dlx3, Osx, Runx2, and others, to promote the differentiation of dental pulp mesenchymal cells into odontoblasts and downregulated gene expressions, such as those of DSPP and DMP1. Dysregulated BMP signaling causes a number of tooth disorders in humans. Mutation or knockout of BMP signaling-associated genes in mice results in dentin defects which enable a better understanding of the BMP signaling networks underlying odontoblast differentiation and dentin formation. This review summarizes the recent advances in our understanding of BMP signaling in odontoblast differentiation and dentin formation. It includes discussion of the expression of BMPs, their receptors, and the implicated downstream genes during dentinogenesis. In addition, the structures of BMPs, BMP receptors, antagonists, and dysregulation of BMP signaling pathways associated with dentin defects are described. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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26 pages, 2850 KiB  
Review
Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology
by Daisy Y. Shu and Frank J. Lovicu
Cells 2021, 10(10), 2604; https://doi.org/10.3390/cells10102604 - 30 Sep 2021
Cited by 20 | Viewed by 5450
Abstract
Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell [...] Read more.
Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell proliferation, differentiation and morphogenesis, throughout the body. In the ocular lens, BMPs are important in orchestrating fundamental developmental processes such as induction of lens morphogenesis, and specialized differentiation of its fiber cells. Moreover, BMPs have been reported to facilitate regeneration of the lens, as well as abrogate pathological processes such as TGFβ-induced epithelial-mesenchymal transition (EMT) and apoptosis. In this review, we summarize recent insights in this topic and discuss the complexities of BMP-signaling including the role of individual BMP ligands, receptors, extracellular antagonists and cross-talk between canonical and non-canonical BMP-signaling cascades in the lens. By understanding the molecular mechanisms underlying BMP activity, we can advance their potential therapeutic role in cataract prevention and lens regeneration. Full article
(This article belongs to the Special Issue Bone Morphogenetic Protein (BMP) Signaling in Health and Diseases)
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