Inhibitors of the bone morphogenetic protein (BMP) signaling pathway: a patent review (2008-2015)

2016 ◽  
Vol 26 (10) ◽  
pp. 1115-1128 ◽  
Author(s):  
Corey R. Hopkins
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
Morphogenetic Protein ◽  
Patent Review

scholarly journals BMP action in skeletogenesis involves attenuation of retinoid signaling

2006 ◽  
Vol 174 (1) ◽  
pp. 101-113 ◽  
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.

scholarly journals Inhibition of MicroRNA-302 (miR-302) by Bone Morphogenetic Protein 4 (BMP4) Facilitates the BMP Signaling Pathway

2012 ◽  
Vol 287 (46) ◽  
pp. 38656-38664 ◽  
Author(s):  
Hara Kang ◽  
Justin Louie ◽  
Alexandra Weisman ◽  
Jessica Sheu-Gruttadauria ◽  
Brandi N. Davis-Dusenbery ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 4 ◽  
Morphogenetic Protein

scholarly journals Up-regulation of bone morphogenetic protein and its signaling molecules following castration of bulls and their association with intramuscular fat content in Korean cattle

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Da Jin Sol Jung ◽  
Myunggi Baik
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Fiber ◽  
Fiber Type ◽  
Glycolytic Enzyme ◽  
Bmp Signaling ◽  
Muscle Fiber Type ◽  
Mrna Levels ◽  
Korean Cattle ◽  
Morphogenetic Protein

AbstractWe evaluated whether castration affects bone morphogenetic protein 2 (BMP2) level and the expression of its signaling molecules in Korean cattle bulls. We also checked whether castration affects the expression of muscle fiber type and oxidative and glycolytic enzyme genes. Enzyme-linked immunosorbent assays revealed that steers had higher plasma BMP2 and leptin concentrations than bulls. Quantitative real-time PCR showed that steers had higher mRNA levels of the lysyl oxidase gene, a downstream target of the BMP signaling pathway, in the longissimus thoracis (LT) muscle. Steers had higher adipogenic peroxisome proliferator-activated receptor gamma and lipogenic fatty acid binding protein 4 mRNA levels in the LT than bulls. Steers had lower mRNA levels for several muscle fiber type 1 genes and fiber type 2A myosin heavy chain 2 gene than bulls. Steers had higher mRNA levels of the glycolytic enzyme phosphoglycerate kinase 1 gene than bulls. Transcript levels of oxidative enzyme genes did not differ between bulls and steers. Regression analysis revealed a positive association between plasma BMP2 levels and intramuscular fat (IMF) content in the steer group. These findings suggest that upregulation of the BMP signaling pathway in response to castration induces increased adipogenic gene expression, contributing to the increased IMF deposition observed in castrated animals.

scholarly journals The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

2013 ◽  
Vol 203 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Catherine E. Winbanks ◽  
Justin L. Chen ◽  
Hongwei Qian ◽  
Yingying Liu ◽  
Bianca C. Bernardo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Positive Regulator ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.

scholarly journals Smad1 and Smad5 differentially regulate embryonic hematopoiesis

Blood ◽  
2007 ◽  
Vol 110 (12) ◽  
pp. 3881-3890 ◽  
Author(s):  
Lisa J. McReynolds ◽  
Sunny Gupta ◽  
Maria E. Figueroa ◽  
Mary C. Mullins ◽  
Todd Evans
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
Loss Of Function ◽  
Normal Numbers ◽  
Hematopoietic Progenitors ◽  
Microarray Experiments ◽  
Morphogenetic Protein ◽  
Primitive Erythropoiesis ◽  
Related Proteins

Abstract The bone morphogenetic protein (BMP) signaling pathway regulates multiple steps of hematopoiesis, mediated through receptor-regulated Smads, including Smad1 and Smad5. Here, we use loss-of-function approaches in zebrafish to compare the roles of Smad1 and Smad5 during embryonic hematopoiesis. We show that knockdown of Smad1 or Smad5 generates distinct and even opposite hematopoietic phenotypes. Embryos depleted for Smad1 have an increased number of primitive erythrocytes, but fail to produce mature embryonic macrophages. In contrast, Smad5-depleted embryos are defective in primitive erythropoiesis, yet have normal numbers of macrophages. Loss of either Smad1 or Smad5 causes a failure in the generation of definitive hematopoietic progenitors. To investigate the mechanism behind these phenotypes, we used rescue experiments and found that Smad5 is unable to rescue the Smad1 loss-of-function phenotype, indicating that the 2 highly related proteins have inherently distinct activities. Microarray experiments revealed that the 2 proteins redundantly regulate the key initiators of the hemato-vascular program, including scl, lmo2, and gfi1. However, each also regulates a remarkably distinct genetic program, with Smad5 uniquely regulating the BMP signaling pathway itself. Our results suggest that specificity of BMP signaling output, with respect to hematopoiesis, can be explained by differential functions of Smad1 and Smad5.

scholarly journals Neuroligin 4 regulates synaptic growth via the bone morphogenetic protein (BMP) signaling pathway at theDrosophilaneuromuscular junction

2017 ◽  
Vol 292 (44) ◽  
pp. 17991-18005 ◽  
Author(s):  
Xinwang Zhang ◽  
Menglong Rui ◽  
Guangmin Gan ◽  
Cong Huang ◽  
Jukang Yi ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Bmp Signaling ◽  
Synaptic Growth ◽  
Morphogenetic Protein

scholarly journals Bone Morphogenetic Proteins 2/4 Are Upregulated during the Early Development of Vascular Calcification in Chronic Kidney Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Xiao Wei ◽  
Weihua Wu ◽  
Li Li ◽  
Jiaru Lin ◽  
Qi Liu ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Early Development ◽  
Vascular Calcification ◽  
Mrna Level ◽  
Calcium Content ◽  
Bmp Signaling ◽  
Morphogenetic Protein

Vascular calcification is a main cause of increased cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. This study aimed to investigate the role of the bone morphogenetic protein (BMP) signaling pathway in the early development of vascular calcification in CKD. A CKD vascular calcification rat model was established by providing rats with a 1.8% high-phosphorus diet and an intragastric administration of 2.5% adenine suspension. The kidney and aortic pathologies were analyzed. Blood biochemical indicators, serum BMP-2 and BMP-4 levels, and aortic calcium content were determined. The expression levels of BMP-2, BMP-4, bone morphogenetic protein receptor-IA (BMPR-IA), and matrix Gla protein (MGP) in aorta were examined by quantitative real-time polymerase chain reaction and immunohistochemistry. Compared with the normal control (Nor) rats, the CKD rats exhibited a significantly decreased body weight and an increased kidney weight as well as abnormal renal function and calcium-phosphorus metabolism. Aortic von Kossa and Alizarin red staining showed massive granular deposition and formation of calcified nodules in aorta at 8 weeks. The aortic calcium content was significantly increased, which was positively correlated with the serum BMP-2 (r=0.929; P<0.01) and serum BMP-4 (r=0.702; P<0.01) levels in CKD rats. The rat aortic BMP-2 mRNA level in the CKD rats was persistently increased, and the BMP-4 mRNA level was prominently increased at the 4th week, declining thereafter. Strong staining of BMP-2, BMP-4, BMPR-IA, and MGP proteins was observed in the tunica media of the aorta from the 4th week after model induction. In conclusion, activation of the BMP signaling pathway is involved in the early development of vascular calcification in CKD. Therefore, elevated serum BMP-2 and BMP-4 levels may serve as serum markers for CKD vascular calcification.

scholarly journals Activation of the Bone Morphogenetic Protein Signaling Pathway Induces Inhibin βB-Subunit mRNA and Secreted Inhibin B Levels in Cultured Human Granulosa-Luteal Cells

2002 ◽  
Vol 87 (3) ◽  
pp. 1254-1261 ◽  
Author(s):  
Risto Jaatinen ◽  
Jonas Bondestam ◽  
Taneli Raivio ◽  
Kristiina Hildén ◽  
Leo Dunkel ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Granulosa Cell ◽  
Bmp Signaling ◽  
Inhibin B ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Subunit Mrna ◽  
Morphogenetic Protein

During the human menstrual cycle the circulating levels of inhibin B, a dimer of inhibin α- and βB-subunits, fluctuate in a fashion distinct from that of inhibin A, the α-βA-subunit dimer. This suggests that human inhibin subunits are each regulated in a distinct manner in human ovarian granulosa cells by endocrine and local factors. We have previously shown using cultures of human granulosa-luteal (hGL) cells that gonadotropins stimulate the steady state mRNA levels of inhibin α- and βA-subunits, but not those of the βB-subunit, which, on the other hand, are up-regulated by, for instance, activin and TGFβ. We recently identified the TGFβ gene family member bone morphogenetic protein-3 (BMP-3) as a granulosa cell-derived growth factor, but whether BMP-3 or other structurally related BMPs regulate human granulosa cell inhibin production is not known. We show here that hGL cells express mRNAs for distinct serine/threonine kinase receptors (BMP-RIA and BMP-RII) and Smad signaling proteins (Smad1, Smad4, and Smad5) involved in the mediation of cellular effects of BMPs. Subsequently, we determined in hGL cell cultures the effects of distinct members of the BMP family previously found to be expressed in mammalian ovaries. Recombinant BMP-2 induces potently in a time- and concentration-dependent manner the expression of the inhibin βB-subunit mRNAs in hGL cells without affecting the levels of α- or βA-subunit mRNAs. BMP-6 has a similar, but weaker, effect than BMP-2, whereas BMP-3 and its close homolog, BMP-3b (also known as growth differentiation factor-10) had no effect on inhibin subunit mRNA expression. hCG treatment of hGL cells was previously shown to abolish the stimulatory effect of activin on βB-subunit mRNA levels, and here hCG is also shown to suppress the effect of BMP-2. Furthermore, BMP-2 stimulates hGL cell secreted dimeric inhibin B levels in a concentration-dependent manner. Depending on the experiment, maximal increases in inhibin B levels of 6- to 28-fold above basal levels were detected during a 72-h culture period. We conclude that activation of the BMP-signaling pathway in hGL cells stimulates inhibin βB-subunit mRNA levels and leads at the protein level to a dramatic stimulation of secreted inhibin B dimers. Our results are consistent with the suggestion that in addition to the distinct activin- and TGFβ-activated signaling pathways, the BMP-activated pathway is likely to be implicated in the complex regulation of inhibins in the human ovary.

Sign in / Sign up

Export Citation Format

Share Document