A Survey of Strategies to Modulate the Bone Morphogenetic Protein Signaling Pathway: Current and Future Perspectives

Lowery, Jonathan W.; Brookshire, Brice; Rosen, Vicki

doi:10.1155/2016/7290686

Cited by 29 publications

(44 citation statements)

References 227 publications

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“…Misregulation of BMP signaling can cause a variety of disorders in humans (Brazil et al 2015;Salazar et al 2016;Wu et al 2016). Previous studies have demonstrated that BMP signaling can be regulated at many levels, both extracellularly and intracellularly (Bragdon et al 2011;Lowery et al 2016;Sedlmeier and Sleeman 2017). The nematode Caenorhabditis elegans provides a useful system for identifying factors that modulate the BMP pathway.…”

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confidence: 99%

The Caenorhabditis elegans SMOC-1 Protein Acts Cell Nonautonomously To Promote Bone Morphogenetic Protein Signaling

DeGroot¹,

Shi²,

Eastman³

et al. 2018

Genetics

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Bone morphogenetic protein (BMP) signaling regulates many different developmental and homeostatic processes in metazoans. The BMP pathway is conserved in Caenorhabditis elegans, and is known to regulate body size and mesoderm development. We have identified the C. elegans smoc-1 (Secreted MOdular Calcium-binding protein-1) gene as a new player in the BMP pathway. smoc-1(0) mutants have a small body size, while overexpression of smoc-1 leads to a long body size and increased expression of the RAD-SMAD (reporter acting downstream of SMAD) BMP reporter, suggesting that SMOC-1 acts as a positive modulator of BMP signaling. Using double-mutant analysis, we showed that SMOC-1 antagonizes the function of the glypican LON-2 and acts through the BMP ligand DBL-1 to regulate BMP signaling. Moreover, SMOC-1 appears to specifically regulate BMP signaling without significant involvement in a TGFb-like pathway that regulates dauer development. We found that smoc-1 is expressed in multiple tissues, including cells of the pharynx, intestine, and posterior hypodermis, and that the expression of smoc-1 in the intestine is positively regulated by BMP signaling. We further established that SMOC-1 functions cell nonautonomously to regulate body size. Human SMOC1 and SMOC2 can each partially rescue the smoc-1(0) mutant phenotype, suggesting that SMOC-1's function in modulating BMP signaling is evolutionarily conserved. Together, our findings highlight a conserved role of SMOC proteins in modulating BMP signaling in metazoans.B ONE morphogenetic proteins (BMPs) are highly conserved signaling molecules that mediate cell-to-cell communication. The BMP signaling cascade is initiated when the BMP ligands bind to the membrane-bound receptor kinases, upon which the type II receptor phosphorylates the type I receptors. The signaling cascade is then transduced within the receiving cell as the receptor-associated Smads (R-Smads) are activated via phosphorylation by the type I receptor. Activated R-Smads complex together with common mediator Smads (co-Smads) and other transcription factors to regulate the transcription of downstream genes (Katagiri and Watabe 2016). BMPs regulate fundamental cellular processes, including cell migration, cell proliferation, cell fate

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confidence: 99%

The Caenorhabditis elegans SMOC-1 Protein Acts Cell Nonautonomously To Promote Bone Morphogenetic Protein Signaling

DeGroot¹,

Shi²,

Eastman³

et al. 2018

Genetics

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“…Here, we wish to provide a brief outline of strategies currently available to modulate the BMP pathway in vivo, starting from upstream of receptor engagement and moving downstream from receptor and effector activity (Table 2). A greatly expanded discussion of this topic with detailed applications has been published recently (Lowery et al 2016).…”

Section: Current Strategies To Modulate Bmp Pathway Activitymentioning

confidence: 99%

“…Additionally, several BMP-inspired ligands have been developed with enhanced signaling ability compared with naturally occurring BMP ligands (Table 3). Specific applications involve engineered BMP ligands and are highlighted in a recent review (Lowery et al 2016). Delivery of cDNAs encoding these natural or engineered BMP ligands for synthesis in vivo has also been achieved in numerous settings (Lowery et al 2016).…”

Section: Modulation Of Bmp Activity In the Extracellular Environmentmentioning

confidence: 99%

“…Specific applications involve engineered BMP ligands and are highlighted in a recent review (Lowery et al 2016). Delivery of cDNAs encoding these natural or engineered BMP ligands for synthesis in vivo has also been achieved in numerous settings (Lowery et al 2016). Additionally, several FDA approved drugs regulate expression of BMP ligands or potentiate the BMP pathway, including the statin drugs lovastatin and simvastatin (Sugiyama et al 2000;Maeda et al 2001;Song et al 2003;Bradley et al 2007;Kodach et al 2007;Zhang and Lin 2008), the Rho-kinase inhibitor fasudil (Kanazawa et al 2009(Kanazawa et al , 2010, and the phosphodiesterase inhibitors pentoxifylline, rolipram, and sildenafil (Horiuchi et al 2001;Horiuchi et al 2002;Rondelet et al 2010;Tokuhara et al 2010;Yen et al 2010;Munisso et al 2012;Yang et al 2013b).…”

Section: Modulation Of Bmp Activity In the Extracellular Environmentmentioning

confidence: 99%

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Bone Morphogenetic Protein–Based Therapeutic Approaches

Lowery

Rosen

2017

Cold Spring Harb Perspect Biol

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Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor (TGF)-β family of ligands and exert most of their effects through the canonical effectors Smad1, 5, and 8. Appropriate regulation of BMP signaling is critical for the development and homeostasis of numerous human organ systems. Aberrations in BMP pathways or their regulation are increasingly associated with diverse human pathologies, and there is an urgent and growing need to develop effective approaches to modulate BMP signaling in the clinic. In this review, we provide a wide perspective on diseases and/or conditions associated with dysregulated BMP signal transduction, outline the current strategies available to modulate BMP pathways, highlight emerging second-generation technologies, and postulate prospective avenues for future investigation.

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“…6). BMPs and activins can be targeted clinically by use of soluble decoy receptors (for a recent 16 review, see (Lowery et al, 2016)). This approach is based on the ligands' affinities to receptor 17 and may not be a specific way of targeting a particular signaling pathway.…”

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confidence: 99%