scholarly journals Bone morphogenetic protein 2 and activin A synergistically stimulate follicle-stimulating hormone β subunit transcription

2007 ◽  
Vol 38 (2) ◽  
pp. 315-330 ◽  
Author(s):  
Katharine B Lee ◽  
Vishal Khivansara ◽  
Michelle M Santos ◽  
Pankaj Lamba ◽  
Tony Yuen ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Activin A ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Mrna Levels ◽  
Signaling Mechanism ◽  
Morphogenetic Protein

Transforming growth factor β superfamily ligands regulate pituitary FSH production and secretion. The best-described examples are the activins and inhibins, which respectively stimulate and hinder Fshb subunit transcription in gonadotrope cells. More recently, members of the bone morphogenetic protein (BMP) sub-family were shown to regulate FSH production in a manner analogous to the activins. Here, we used the murine gonadotrope cell line, LβT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LβT2 cells, Bmp2 mRNA was readily detected in adult murine pituitary gland. Recombinant BMP2 stimulated Fshb promoter-reporter activity, although its effects were weaker than those of equimolar activin A or B. BMP4 stimulated transcription comparably with BMP2, but BMPs 6 and 7 were about tenfold less potent. Remarkably, BMP2 and activin A synergistically upregulated Fshb transcription and endogenous Fshb mRNA levels in LβT2 cells. Although functionally cooperative, the two ligands appeared to use distinct intracellular mechanisms to mediate their responses because neither ligand altered the timing or magnitude of the other’s effects. Receptor overexpression analyses suggested that BMP2 may preferentially signal through complexes of the type II receptor, BMPR2, and the type I receptor, activin receptor like kinase (ALK2; Acvr1), to stimulate Fshb transcription. BMP2 rapidly activated the Smad1/5/8 intracellular signaling cascade and Smad8 overexpression potentiated BMP2’s effects. In summary, BMPs regulate Fshb transcription in LβT2 cells and can amplify the already robust effects of the activins through a distinct signaling mechanism. Because BMP2 is expressed in the adult mouse pituitary, it may act as critical paracrine co-regulator of FSH synthesis by gonadotropes.

scholarly journals Myostatin/Activin-A Signaling in the Vessel Wall and Vascular Calcification

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2070
Author(s):  
Pasquale Esposito ◽  
Daniela Verzola ◽  
Daniela Picciotto ◽  
Leda Cipriani ◽  
Francesca Viazzi ◽  
...  
Keyword(s):  
Vascular Calcification ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Vascular Inflammation ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Activin A ◽  
Premature Aging ◽  
High Morbidity ◽  
Type I

A current hypothesis is that transforming growth factor-β signaling ligands, such as activin-A and myostatin, play a role in vascular damage in atherosclerosis and chronic kidney disease (CKD). Myostatin and activin-A bind with different affinity the activin receptors (type I or II), activating distinct intracellular signaling pathways and finally leading to modulation of gene expression. Myostatin and activin-A are expressed by different cell types and tissues, including muscle, kidney, reproductive system, immune cells, heart, and vessels, where they exert pleiotropic effects. In arterial vessels, experimental evidence indicates that myostatin may mostly promote vascular inflammation and premature aging, while activin-A is involved in the pathogenesis of vascular calcification and CKD-related mineral bone disorders. In this review, we discuss novel insights into the biology and physiology of the role played by myostatin and activin in the vascular wall, focusing on the experimental and clinical data, which suggest the involvement of these molecules in vascular remodeling and calcification processes. Moreover, we describe the strategies that have been used to modulate the activin downward signal. Understanding the role of myostatin/activin signaling in vascular disease and bone metabolism may provide novel therapeutic opportunities to improve the treatment of conditions still associated with high morbidity and mortality.

scholarly journals Bone Morphogenetic Protein-2 Antagonizes Renal Interstitial Fibrosis by Promoting Catabolism of Type I Transforming Growth Factor-β Receptors

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 727-740 ◽  
Author(s):  
Yu-Lin Yang ◽  
Yi-Shiuan Liu ◽  
Lea-Yea Chuang ◽  
Jinn-Yuh Guh ◽  
Tao-Chen Lee ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Ureteral Obstruction ◽  
Time Course ◽  
Transforming Growth Factor ◽  
Interstitial Fibrosis ◽  
Unilateral Ureteral Obstruction ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Morphogenetic Protein ◽  
Tgf Β1

TGF-β is a therapeutic target for renal fibrosis. Scientists have long sought ways to antagonize TGF-β to ameliorate diabetic nephropathy. Bone morphogenetic protein (BMP-2) is a member of the TGF-β superfamily and is highly regulated in the kidney. Thus, the role of BMP-2 was investigated in NRK-49F cells (rat fibroblasts). We showed that TGF-β1 induces an increase in fibronectin. Treatment with exogenous BMP-2 or pCMV-BMP-2 significantly reversed the TGF-β1-induced increase in fibronectin concomitant with a significant decrease in type I TGF-β receptors (TGF-β RI). Moreover, BMP-2 significantly shortened the half-life of TGF-β RI. These results are related to proteosomal activation because MG132, a proteasome inhibitor, abolished BMP-2-mediated degradation of TGF-β RI. This was confirmed because BMP-2 time course dependently enhanced the ubiquitination level of TGF-β RI. In addition, Smads would seem to be involved in the interaction of BMP-2 and TGF-β. We demonstrated that BMP-2 significantly reversed the TGF-β1-induced increase in pSmad2/3 and reversed the TGF-β1-induced decrease in inhibitory Smad7. Most importantly, Smad7 small interfering RNA abolished the BMP-2-induced decrease in TGF-β RI. We evaluated the clinical efficacy of BMP-2 using unilateral ureteral obstruction rats. BMP-2 was administered ip for 7 d. In the unilateral ureteral obstruction kidneys, interstitial fibrosis was prominent. However, treatment with BMP-2 dramatically reduced Masson’s trichrome staining (collagen) in the interstitial and tubular areas of the kidneys concomitantly with a reduction in TGF-β RI. These results suggest that BMP-2 acts as a novel fibrosis antagonizing cytokine partly by down-regulating TGF-β RI and Smads. Bone morphogenetic protein-2 can antagonize TGF-β-inducing cellular fibrosis by intervening post-receptors signaling, thus disclosing an application of therapeutical potential against fibrosis disorders.

Bone Morphogenetic Protein-2 Inhibits Differentiation and Mineralization of Cementoblasts in vitro

2003 ◽  
Vol 82 (1) ◽  
pp. 23-27 ◽  
Author(s):  
M. Zhao ◽  
J.E. Berry ◽  
M.J. Somerman
Keyword(s):  
Bone Morphogenetic Protein ◽  
Type I Collagen ◽  
Bone Morphogenetic Protein 2 ◽  
Nodule Formation ◽  
Type I ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Morphogenetic Protein ◽  
Regenerative Therapies

As an approach for improving the outcome and predictability of periodontal regenerative therapies, we have focused on determining the responses of cells within the local environment to putative regenerative factors. This study examined the effects of bone morphogenetic protein-2 (BMP-2) on murine cementoblasts in vitro. Northern blot analysis indicated that BMP-2 decreased mRNA levels of bone sialoprotein and type I collagen dose-dependently (10–300 ng/mL). At low doses, up to 100 ng/mL, BMP-2 had no effect on transcripts for osteocalcin and osteopontin, whereas at 300 ng/mL, BMP-2 greatly increased expression of these two genes. BMP-2 also inhibited cementoblast-mediated mineral nodule formation in a dose-dependent manner (inhibition was noted at 10 ng/mL). Noggin reversed the effects of BMP-2 on gene expression and on mineralization. These findings reflect the diverse responses of periodontal cells to BMP-2 and highlight the need to consider the complexity of factors involved in designing predictable regenerative therapies.

scholarly journals Smad6 Recruits Transcription Corepressor CtBP To Repress Bone Morphogenetic Protein-Induced Transcription

2003 ◽  
Vol 23 (24) ◽  
pp. 9081-9093 ◽  
Author(s):  
Xia Lin ◽  
Yao-Yun Liang ◽  
Baohua Sun ◽  
Min Liang ◽  
Yujiang Shi ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Feedback Mechanism ◽  
Binding Motif ◽  
Physical Interaction ◽  
Type I ◽  
Negative Feedback Mechanism ◽  
Morphogenetic Protein ◽  
Repressor Activity

ABSTRACT Smad6 and Smad7 are inhibitory Smads induced by transforming growth factor β-Smad signal transduction pathways in a negative-feedback mechanism. Previously it has been thought that inhibitory Smads bind to the type I receptor and block the phosphorylation of receptor-activated Smads, thereby inhibiting the initiation of Smad signaling. Conversely, few studies have suggested the possible nuclear functions of inhibitory Smads. Here, we present compelling evidence demonstrating that Smad6 repressed bone morphogenetic protein-induced Id1 transcription through recruiting transcriptional corepressor C-terminal binding protein (CtBP). A consensus CtBP-binding motif, PLDLS, was identified in the linker region of Smad6. Our findings show that mutation in the motif abolished the Smad6 binding to CtBP and subsequently its repressor activity of transcription. We conclude that the nuclear functions and physical interaction of Smad6 and CtBP provide a novel mechanism for the transcriptional regulation by inhibitory Smads.

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