Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Lowery, Jonathan W.; Intini, Giuseppe; Gamer, Laura W.; Lotinun, Sutada; Salazar, Valerie S.; Ote, Satoshi; Cox, Karen; Baron, Roland; Rosen, Vicki

doi:10.1242/jcs.156737

Cited by 47 publications

(26 citation statements)

References 85 publications

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“…Generally, the finding that activin can act as an inhibitor of canonical BMP signaling via ACVR1 calls for a reassessment of existing data obtained using activins. We note that the reciprocal situation, where BMPs compete with activins for shared type II receptors, has already been reported (33). …”

Section: Discussionsupporting

confidence: 64%

ACVR1 ^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

et al. 2015

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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodically exuberant heterotopic ossification (HO), whereby skeletal muscle is abnormally converted into misplaced, but histologically normal bone. This HO leads to progressive immobility with catastrophic consequences, including death by asphyxiation. FOP results from mutations in the intracellular domain of the type I BMP (bone morphogenetic protein) receptor ACVR1; the most common mutation alters arginine 206 to histidine (ACVR1R206H) and has been thought to drive inappropriate bone formation as a result of receptor hyperactivity. We unexpectedly found that this mutation rendered ACVR1 responsive to the activin family of ligands, which generally antagonize BMP signaling through ACVR1 but cannot normally induce bone formation. To test the implications of this finding in vivo, we engineered mice to carry the Acvr1R206H mutation. Because mice that constitutively express Acvr1[R206H] die perinatally, we generated a genetically humanized conditional-on knock-in model for this mutation. When Acvr1[R206H] expression was induced, mice developed HO resembling that of FOP; HO could also be triggered by activin A administration in this mouse model of FOP but not in wild-type controls. Finally, HO was blocked by broad-acting BMP blockers, as well as by a fully human antibody specific to activin A. Our results suggest that ACVR1R206H causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, demonstrating that this ligand is necessary and sufficient for driving HO in a genetically accurate model of FOP; hence, our human antibody to activin A represents a potential therapeutic approach for FOP.

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Section: Discussionsupporting

confidence: 64%

ACVR1 ^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

et al. 2015

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“…Extending the model to include the TGF-β ligands could be used to understand newly discovered ligand-level competition between the two branches of this signaling pathway (Hatsell et al, 2015; Lowery et al, 2015; Olsen et al, 2015) and incorporate them into a single framework. More generally, Wnt, FGF, JAK-STAT, Eph-Ephrin, and other signaling pathways also exhibit promiscuous interactions between multiple ligand, receptor and co-receptor variants and may function according to similar principles (Jørgensen et al, 2009; Murray, 2007; Wodarz and Nusse, 1998).…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Signal Perception in the BMP Pathway

Antebi

Linton

Klumpe

et al. 2017

Cell

215

282

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Summary The Bone Morphogenetic Protein (BMP) signaling pathway comprises multiple ligands and receptors that interact promiscuously with one another, and typically appear in combinations. This feature is often explained in terms of redundancy and regulatory flexibility, but it has remained unclear what signal processing capabilities it provides. Here, we show that the BMP pathway processes multi-ligand inputs using a specific repertoire of computations, including ratiometric sensing, balance detection and imbalance detection. These computations operate on the relative levels of different ligands, and can arise directly from competitive receptor-ligand interactions. Furthermore, cells can select different computations to perform on the same ligand combination through expression of alternative sets of receptor variants. These results provide a direct signal processing role for promiscuous receptor-ligand interactions, and establish operational principles for quantitatively controlling cells with BMP ligands. Similar principles could apply to other promiscuous signaling pathways.

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“…Inhibin A, an activin A-related ligand that lacks signaling activity, inhibited BMP responses by competing for type II receptor binding (35)(36)(37). Binding competition was also proposed for some BMPs together with type II receptors (69), for activin A combined with type I receptors (70), and for activin A with BMP-9 (33). We propose binding competition and signaling antagonism is a common regulatory mechanism in the TGF-␤ family enabled by receptor promiscuity and binding site conservation (19).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding

Aykul

Martı́nez-Hackert

2016

Journal of Biological Chemistry

108

105

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Transforming growth factor-␤ (TGF-␤) family ligands are pleiotropic cytokines. Their physiological activities are not determined by a simple coupling of stimulus and response, but depend critically on context, i.e. the interplay of receptors, ligands, and regulators that form the TGF-␤ signal transduction system of a cell or tissue. How these different components combine to regulate signaling activities remains poorly understood. Here, we describe a ligand-mediated mechanism of signaling regulation. Based on the observation that the type II TGF-␤ family receptors ActRIIA, ActRIIB, and BMPRII interact with a large group of overlapping ligands at overlapping epitopes, we hypothesized high affinity ligands compete with low affinity ligands for receptor binding and signaling. We show activin A and other high affinity ligands directly inhibited signaling by the low affinity ligands BMP-2, BMP-7, and BMP-9. We demonstrate activin A functions as a competitive inhibitor that blocks the ligand binding epitope on type II receptors. We propose binding competition and signaling antagonism are integral functions of the TGF-␤ signal transduction system. These functions could help explain how activin A modulates physiological signaling during extraordinary cellular responses, such as injury and wound healing, and how activin A could elicit disease phenotypes such as cancer-related muscle wasting and fibrosis.Transforming growth factor-␤ (TGF-␤) family signaling pathways play fundamentally important roles in stem cell fate determination, embryonic development, organogenesis, immunity, and cancer (1-3). The basic principles underlying TGF-␤ family action are well established. A dimeric ligand binds two type I and two type II receptors to form a hexameric complex, thus initiating a signaling cascade that leads to phosphorylation of SMAD transcription factors, their translocation to the nucleus, and expression of target genes (4 -9). Although this simple mechanism completely describes the molecular basis of signaling and response, it fails to explain the complex and sometimes opposite responses elicited by many TGF-␤ family ligands. For example, some TGF-␤ family ligands can both inhibit and promote cell growth, maintain pluripotency, and induce differentiation, and both suppress and activate tumor cells. These paradoxical effects have supported the idea that cellular responses to a TGF-␤ family ligand depend not only on the ligand-induced signaling cascade but also on the cellular context, i.e. the molecular interplay of all the components that form the TGF-␤ signal transduction system of a particular cell type or tissue (10 -14).In humans, the TGF-␤ family consists of 33 ligand genes (TGF-␤s, activins, bone morphogenetic proteins (BMPs), 2 growth and differentiation factors (GDFs, nodal and lefty), seven type I receptors, (ALK1-7), five type II receptors (ActRIIA, ActRIIB, BMPRII, TGF␤RII, and AMHRII), as well as a number of co-receptors, regulators, and intracellular SMAD transcription factors (3, 15). A distinct feature of the...

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Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Cited by 47 publications

References 85 publications

ACVR1 ^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

ACVR1 ^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

Combinatorial Signal Perception in the BMP Pathway

Transforming Growth Factor-β Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding

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Loss of BMPR2 leads to high bone mass due to increased osteoblast activity

Cited by 47 publications

References 85 publications

ACVR1 R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

ACVR1 R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

Combinatorial Signal Perception in the BMP Pathway

Transforming Growth Factor-β Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding

Contact Info

Product

Resources

About

ACVR1 ^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A

ACVR1 ^R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A