Initiation of Smad-Dependent and Smad-Independent Signaling via Distinct BMP-Receptor Complexes

Haßel, Sylke; Schmitt, Simone; Hartung, Anke; Roth, Martin; Nohe, Anja; Petersen, Nils O.; Ehrlich, Marcelo; Henis, Yoav I.; Sebald, Walter; Knaus, Petra

doi:10.2106/00004623-200300003-00009

Cited by 99 publications

(79 citation statements)

References 22 publications

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“…These data suggest that BMP2 may signal through pre-assembled receptor complexes to stimulate the Fshb promoter. Consistent with this idea, previous reports show that BMP2 can signal through pre-assembled complexes of BMPR2 and ALK3 to activate the Smad1/5/8 pathway and through ligand-induced signaling complexes to activate a Smadindependent, p38 MAPK, pathway (Nohe et al 2002, Hassel et al 2003. Indeed, here we observe that BMP2 rapidly activates Smad1/5/8, but not p38, phosphorylation.…”

Section: Discussionsupporting

confidence: 92%

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

Lee

Khivansara²,

Santos³

et al. 2007

Journal of Molecular Endocrinology

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Transforming growth factor b 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, LbT2, to investigate mechanisms through which BMP2 regulates the Fshb gene. Although expressed at low levels in LbT2 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 LbT2 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 LbT2 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.

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Section: Discussionsupporting

confidence: 92%

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

Lee

Khivansara²,

Santos³

et al. 2007

Journal of Molecular Endocrinology

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“…Our findings are consistent with those of previous reports in which muscle injury and associated inflammatory changes were reported as sufficient to trigger the development of ectopic bone in the setting of increased BMP expression [25,32]. Several human and animal studies have further implicated the role of BMPs and their downstream signaling pathways in the pathogenesis of HO [21,24,53]. The upregulation of SMAD1, a gene encoding protein that serves as a signal transducer and transcriptional modulator of BMP signaling, further supports this observation [47].…”

Section: Functional Protein Expression and Heterotopic Ossificationsupporting

confidence: 92%

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

Evans

Potter

Brown

et al. 2013

Clin Orthop Relat Res

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Background Heterotopic ossification (HO) is a frequent complication of modern wartime extremity injuries. The biological mechanisms responsible for the development of HO in traumatic wounds remain elusive. Question/purposes The aims of our study were to (1) characterize the expression profile of osteogenesis-related gene transcripts in traumatic war wounds in which HO developed; and (2) determine whether expression at the mRNA level correlated with functional protein expression and HO formation. Methods Biopsy specimens from 54 high-energy penetrating extremity wounds obtained at the initial and final surgical débridements were evaluated. The levels of selected osteogenic-related gene transcripts from RNA extracts were assessed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. As a result of its key role in osteogenesis, the concentration of BMP-2 in the effluent of 29 wounds also was determined. Conclusions Important differences exist in the osteogenic gene expression profile of wounds in which HO developed compared with wounds in which it did not develop. The upregulation of multiple osteogenesis-related gene transcripts indicates the presence of a proosteogenic environment necessary for ectopic bone formation in traumatic wounds.

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“…We have demonstrated that the monocyte adhesiveness both to cultured endothelial cells and vascular endothelial cells in situ was substantially increased by BMP-2 as well as BMP-4 (Figure 6, A-C). Because monocyte adhesion was substantially reduced by pharmacological and molecular inhibition of p42/44 and p38 MAP kinases ( Figure 6, A and D, and Figure 7A) and abolished by inhibition of PKC in endothelial cells both in culture and in intact vessels ( Figure 6, A and D), we propose that in endothelial cells BMP-2/4 activates a PKC-and MAP kinase-dependent pathway, 11,31,32 which results in endothelial activation. This view is supported by previous findings demonstrating that the BMP receptor complex is associated with components of PKC and MAP kinase pathways, which can be activated on BMP-2 binding to its receptor.…”

Section: Discussionmentioning

confidence: 91%

Bone Morphogenetic Protein-2 Induces Proinflammatory Endothelial Phenotype

Csiszár

Ahmad

Smith

et al. 2006

The American Journal of Pathology

138

154

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The transforming growth factor-␤ superfamily member bone morphogenetic protein-2 (BMP-2) is up-regulated in atherosclerotic arteries; however, its effects on the endothelium are not well characterized. Using microdissected coronary arterial endothelial cells (CAECs) and cultured primary CAECs, we demonstrated endothelial mRNA expression of BMP-2 and BMP-4. The proinflammatory cytokine tumor necrosis factor-␣ and H 2 O 2 significantly increased endothelial expression of BMP-2 but not BMP-4. In organ culture, BMP-2 substantially decreased relaxation of rat carotid arteries to acetylcholine and increased production of reactive oxygen species, events inhibited by pharmacologically blocking protein kinase C (PKC) or NAD(P)H oxidase. BMP-2 activated nuclear factor-〉 in CAECs, and BMP-2 and BMP-4 substantially increased adhesion of monocytic THP-1 cells, which was reduced by pharmacologically inhibiting p42/44 MAP kinase pathway (also by siRNA downregulating ERK-1/2) or PKC. Incubation of rat carotid arteries with BMP-2 ex vivo also increased adhesion of mononuclear cells to the endothelium, requiring p42/44 MAP kinase and PKC. Western blotting showed that in CAECs and carotid arteries BMP-2 elicited phosphorylation of p42/44 MAP kinase, which was reduced by blocking MAP kinase kinase and PKC. Collectively, expression of BMP-2 is regulated by proinflammatory stimuli, and increased levels of BMP-2 induce endothelial dysfunction, oxidative stress, and endothelial activation. The cytokine bone morphogenetic protein-2 (BMP-2), a transforming growth factor superfamily member, was originally detected in cartilage and bone 1 ; however, recent studies demonstrated that vascular endothelial and smooth muscle cells are also a significant source of BMPs.2-7 Genetic analysis of patients with primary pulmonary hypertension indicated that a vascular BMP-2/ BMP receptor system plays an important role in vascular physiology.8,9 BMP-2 is known to regulate a host of cellular functions, 2,4,5,10 including cardiovascular development, 10 neovascularization in bone 7 and tumors, 11 and smooth muscle cell chemotaxis.2 Endothelium-derived BMP-2 is osteoinductive 5,7 and hypotheses have been put forward that BMPs may contribute to vascular calcification. 3,5,12 Despite evidence for the physiological/ pathophysiological importance of BMP-2 the regulation of BMP-2 expression and the effects exerted by BMP-2 on endothelial function and phenotype have yet to be clearly elucidated.Previously, we have demonstrated that in coronary arteries in hyperhomocysteinemia vascular inflammation and up-regulation of tumor necrosis factor (TNF)-␣ is associated with an increased vascular BMP-2 expression. 13 Importantly, recent studies confirmed a striking up-regulation of BMPs in atherosclerotic lesions.2-4 BMP-4 (which is related to BMP-2 by its amino acid sequence but is transcribed from an entirely different gene) 4,6 was shown to exert proinflammatory effects by enhancing monocyte adhesion to the endothelium. On the basis of the aforementioned findings we h...

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Initiation of Smad-Dependent and Smad-Independent Signaling via Distinct BMP-Receptor Complexes

Cited by 99 publications

References 22 publications

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

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

Osteogenic Gene Expression Correlates With Development of Heterotopic Ossification in War Wounds

Bone Morphogenetic Protein-2 Induces Proinflammatory Endothelial Phenotype

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