Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases

Given its importance in development and homeostasis, bone morphogenetic protein (BMP) signaling is tightly regulated at the extra- and intracellular level. The extracellular matrix (ECM) was initially thought to act as a passive mechanical barrier that sequesters BMPs. However, a new understanding about how the ECM plays an instructive role in regulating BMP signaling is emerging. In this mini-review, we discuss various ways in which the biochemical and physical properties of the ECM regulate BMP signaling.

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Abstract 17763: Inhibition of Bone Morphogenetic Protein Signaling Reduces Endothelial-Mesenchymal Transition and Vascular Smooth Muscle Cell Calcification Associated with Matrix Gla Protein Deficiency

Circulation ◽

10.1161/circ.130.suppl_2.17763 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Megan F Burke ◽

Caitlin O’Rourke ◽

Trejeeve Martyn ◽

Hannah R Shakartzi ◽

Timothy E Thayer ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Bone Morphogenetic Protein ◽

Vascular Calcification ◽

Bmp Signaling ◽

Matrix Gla Protein ◽

Wild Type ◽

Mesenchymal Transition ◽

Morphogenetic Protein ◽

Endothelial Mesenchymal Transition

Background: Matrix Gla protein (MGP) is an extracellular matrix protein that inhibits bone morphogenetic protein (BMP) signaling in vitro. MGP deficiency induces vascular calcification associated with osteogenic transdifferentiation of endothelial cells (via endothelial-mesenchymal transition, EndMT) and vascular smooth muscle cells (VSMCs). We previously reported that treatment with two pharmacologic inhibitors of BMP signaling reduced aortic calcification in MGP-/- mice. We hypothesized that BMP signaling is essential for EndMT and VSMC osteogenic transdifferentiation induced by MGP deficiency. Methods and Results: Aortic levels of mRNAs encoding markers of osteogenesis (Runx2 and osteopontin) and EndMT (nanog, Sox2, and Oct3/4) were greater in MGP-/- than in wild-type mice (P<0.01 for all). Aortic expression of markers of VSMC differentiation (α-smooth muscle actin, transgelin, and calponin) was less in MGP-/- than in wild-type mice (P<0.001 for all). Treatment of MGP-/- mice with the BMP signaling inhibitor, LDN-193189, reduced expression of both osteogenic and EndMT markers (P<0.05 for all) but did not prevent VSMC de-differentiation. Depletion of MGP in cultured wild-type VSMCs with siRNA specific for MGP (siMGP) was associated with a 30-40% reduction in levels of mRNAs encoding markers of VSMC differentiation (P<0.05 for all), an effect that was not prevented by LDN-193189. Incubation in phosphate-containing media induced greater calcification in siMGP-treated VSMCs than in cells treated with control siRNA (P<0.0001). Treatment with LDN-193189 reduced calcification in siMGP-treated VSMCs (50%, P=0.0003). Conversely, infection of MGP-/- VSMCs with adenovirus specifying MGP increased expression of markers of VSMC differentiation by 60-80% (P<0.01 for all) and decreased calcification by 74% (P=0.03). Conclusions: Inhibition of BMP signaling suppresses osteogenic and EndMT gene programs in MGP-/- mice and reduces calcification of siMGP-treated VSMCs. However, MGP deficiency induces VSMC de-differentiation via a BMP-independent mechanism. These findings suggest that the processes underlying vascular calcification in MGP deficiency are mediated by both BMP signaling-dependent and -independent mechanisms.

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Expression of bone morphogenetic protein receptors in bovine oviductal epithelial cells: Evidence of autocrine BMP signaling

Animal Reproduction Science ◽

10.1016/j.anireprosci.2017.08.006 ◽

2017 ◽

Vol 185 ◽

pp. 89-96 ◽

Cited By ~ 3

Author(s):

Pablo Alberto Valdecantos ◽

Rocío del Carmen Bravo Miana ◽

Elina Vanesa García ◽

Daniela Celeste García ◽

Mariela Roldán-Olarte ◽

...

Keyword(s):

Epithelial Cells ◽

Bone Morphogenetic Protein ◽

Bmp Signaling ◽

Morphogenetic Protein ◽

Protein Receptors ◽

Bone Morphogenetic Protein Receptors

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At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

Genes ◽

10.3390/genes11111371 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1371

Author(s):

Meghan M. Cirulis ◽

Mark W. Dodson ◽

Lynn M. Brown ◽

Samuel M. Brown ◽

Tim Lahm ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Bone Morphogenetic Protein ◽

Pulmonary Arteries ◽

Bmp Signaling ◽

Signaling Cascades ◽

Estrogen Signaling ◽

Protein Receptor ◽

Morphogenetic Protein ◽

Pulmonary Arterial

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

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Bone Morphogenetic Protein Signaling Restricts Proximodistal Extension of the Ventral Fin Fold

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.603306 ◽

2020 ◽

Vol 8 ◽

Author(s):

Jun Ka ◽

Jun-Dae Kim ◽

Boryeong Pak ◽

Orjin Han ◽

Woosoung Choi ◽

...

Keyword(s):

Cell Division ◽

Bone Morphogenetic Protein ◽

Molecular Mechanisms ◽

Bmp Signaling ◽

Protein Signaling ◽

Morphogenetic Protein ◽

Distal Migration ◽

Cellular Behaviors ◽

And Shifts ◽

Migration Of Cells

Unpaired fins, which are the most ancient form of locomotory appendages in chordates, had emerged at least 500 million years ago. While it has been suggested that unpaired fins and paired fins share structural similarities, cellular and molecular mechanisms that regulate the outgrowth of the former have not been fully elucidated yet. Using the ventral fin fold in zebrafish as a model, here, we investigate how the outgrowth of the unpaired fin is modulated. We show that Bone Morphogenetic Protein (BMP) signaling restricts extension of the ventral fin fold along the proximodistal axis by modulating diverse aspects of cellular behaviors. We find that lack of BMP signaling, either caused by genetic or chemical manipulation, prolongs the proliferative capacity of epithelial cells and substantially increases the number of cells within the ventral fin fold. In addition, inhibition of BMP signaling attenuates the innate propensity of cell division along the anteroposterior axis and shifts the orientation of cell division toward the proximodistal axis. Moreover, abrogating BMP signaling appears to induce excessive distal migration of cells within the ventral fin fold, and therefore precipitates extension along the proximodistal axis. Taken together, our data suggest that BMP signaling restricts the outgrowth of the ventral fin fold during zebrafish development.

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Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Blood ◽

10.1182/blood-2010-10-313064 ◽

2011 ◽

Vol 117 (18) ◽

pp. 4915-4923 ◽

Cited By ~ 114

Author(s):

Andrea U. Steinbicker ◽

Chetana Sachidanandan ◽

Ashley J. Vonner ◽

Rushdia Z. Yusuf ◽

Donna Y. Deng ◽

...

Keyword(s):

Bone Morphogenetic Protein ◽

Iron Homeostasis ◽

Iron Bioavailability ◽

Bmp Signaling ◽

Neoplastic Disease ◽

Type I ◽

Hepcidin Expression ◽

Hepatic Expression ◽

Morphogenetic Protein ◽

Anemia Of Inflammation

Abstract Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

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BMP action in skeletogenesis involves attenuation of retinoid signaling

The Journal of Cell Biology ◽

10.1083/jcb.200604150 ◽

2006 ◽

Vol 174 (1) ◽

pp. 101-113 ◽

Cited By ~ 61

Author(s):

Lisa M. Hoffman ◽

Kamal Garcha ◽

Konstantina Karamboulas ◽

Matthew F. Cowan ◽

Linsay M. Drysdale ◽

...

Keyword(s):

Retinoic Acid ◽

Organ Culture ◽

Signaling Pathways ◽

Bone Morphogenetic Protein ◽

Signaling Pathway ◽

Signaling Molecules ◽

Bmp Signaling ◽

Retinoid Signaling ◽

Morphogenetic Protein ◽

Bona Fide

The bone morphogenetic protein (BMP) and growth and differentiation factor (GDF) signaling pathways have well-established and essential roles within the developing skeleton in coordinating the formation of cartilaginous anlagen. However, the identification of bona fide targets that underlie the action of these signaling molecules in chondrogenesis has remained elusive. We have identified the gene for the retinoic acid (RA) synthesis enzyme Aldh1a2 as a principal target of BMP signaling; prochondrogenic BMPs or GDFs lead to attenuation of Aldh1a2 expression and, consequently, to reduced activation of the retinoid signaling pathway. Consistent with this, antagonism of retinoid signaling phenocopies BMP4 action, whereas RA inhibits the chondrogenic stimulatory activity of BMP4. BMP4 also down-regulates Aldh1a2 expression in organ culture and, consistent with this, Aldh1a2 is actively excluded from the developing cartilage anlagens. Collectively, these findings provide novel insights into BMP action and demonstrate that BMP signaling governs the fate of prechondrogenic mesenchyme, at least in part, through regulation of retinoid signaling.

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