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

Lowery JW, Brookshire B, Rosen V - Stem Cells Int (2016)

Bottom Line: In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling.We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation.We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, USA.

ABSTRACT
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-β family of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.

No MeSH data available.


Related in: MedlinePlus

Potential strategies for modulating the BMP pathway. (1–3) The BMP pathway may be activated by exogenous natural or engineered BMP ligands or by expression of such ligands via gene transfer techniques (1). Ligand-induced BMP pathway activation may be inhibited by extracellular ligand traps, such as naturally-occurring antagonists or neutralizing antibodies, via delivery of recombinant protein or expression via gene transfer techniques (2). Endogenous extracellular BMP antagonists, such as Noggin or Chordin, may be inhibited via neutralizing antibodies or small molecules, resulting in increased BMP signaling (3). (4-5) The endogenous BMP pathway inhibitors FKBP12 and Casein Kinase 2 may be inactivated by delivery of FK506 and CK2.3, respectively, thereby increasing signal transduction (4). Alternatively, BMP receptor-mediated activation of the SMAD effectors may be blocked by kinase inhibitors (5). (6-7) Persistence of BMP signaling may be modulated by regulating the SMURF1-mediated ubiquitination of SMAD effector proteins by disrupting SMURF1 interaction with SMADs by small molecule inhibitors (6) or by increasing SMURF1 protein levels (7). (8-9) BMP pathway component expression may be elevated by increasing transcription or alleviating microRNA-mediated translational silencing (8). Alternatively, BMP pathway component levels may be reduced by reducing transcription and/or translation rates (9).
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Related In: Results  -  Collection


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fig1: Potential strategies for modulating the BMP pathway. (1–3) The BMP pathway may be activated by exogenous natural or engineered BMP ligands or by expression of such ligands via gene transfer techniques (1). Ligand-induced BMP pathway activation may be inhibited by extracellular ligand traps, such as naturally-occurring antagonists or neutralizing antibodies, via delivery of recombinant protein or expression via gene transfer techniques (2). Endogenous extracellular BMP antagonists, such as Noggin or Chordin, may be inhibited via neutralizing antibodies or small molecules, resulting in increased BMP signaling (3). (4-5) The endogenous BMP pathway inhibitors FKBP12 and Casein Kinase 2 may be inactivated by delivery of FK506 and CK2.3, respectively, thereby increasing signal transduction (4). Alternatively, BMP receptor-mediated activation of the SMAD effectors may be blocked by kinase inhibitors (5). (6-7) Persistence of BMP signaling may be modulated by regulating the SMURF1-mediated ubiquitination of SMAD effector proteins by disrupting SMURF1 interaction with SMADs by small molecule inhibitors (6) or by increasing SMURF1 protein levels (7). (8-9) BMP pathway component expression may be elevated by increasing transcription or alleviating microRNA-mediated translational silencing (8). Alternatively, BMP pathway component levels may be reduced by reducing transcription and/or translation rates (9).

Mentions: In this section, we highlight several strategies to activate the BMP pathway. These different approaches are schematized in Figure 1.


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

Lowery JW, Brookshire B, Rosen V - Stem Cells Int (2016)

Potential strategies for modulating the BMP pathway. (1–3) The BMP pathway may be activated by exogenous natural or engineered BMP ligands or by expression of such ligands via gene transfer techniques (1). Ligand-induced BMP pathway activation may be inhibited by extracellular ligand traps, such as naturally-occurring antagonists or neutralizing antibodies, via delivery of recombinant protein or expression via gene transfer techniques (2). Endogenous extracellular BMP antagonists, such as Noggin or Chordin, may be inhibited via neutralizing antibodies or small molecules, resulting in increased BMP signaling (3). (4-5) The endogenous BMP pathway inhibitors FKBP12 and Casein Kinase 2 may be inactivated by delivery of FK506 and CK2.3, respectively, thereby increasing signal transduction (4). Alternatively, BMP receptor-mediated activation of the SMAD effectors may be blocked by kinase inhibitors (5). (6-7) Persistence of BMP signaling may be modulated by regulating the SMURF1-mediated ubiquitination of SMAD effector proteins by disrupting SMURF1 interaction with SMADs by small molecule inhibitors (6) or by increasing SMURF1 protein levels (7). (8-9) BMP pathway component expression may be elevated by increasing transcription or alleviating microRNA-mediated translational silencing (8). Alternatively, BMP pathway component levels may be reduced by reducing transcription and/or translation rates (9).
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4940573&req=5

fig1: Potential strategies for modulating the BMP pathway. (1–3) The BMP pathway may be activated by exogenous natural or engineered BMP ligands or by expression of such ligands via gene transfer techniques (1). Ligand-induced BMP pathway activation may be inhibited by extracellular ligand traps, such as naturally-occurring antagonists or neutralizing antibodies, via delivery of recombinant protein or expression via gene transfer techniques (2). Endogenous extracellular BMP antagonists, such as Noggin or Chordin, may be inhibited via neutralizing antibodies or small molecules, resulting in increased BMP signaling (3). (4-5) The endogenous BMP pathway inhibitors FKBP12 and Casein Kinase 2 may be inactivated by delivery of FK506 and CK2.3, respectively, thereby increasing signal transduction (4). Alternatively, BMP receptor-mediated activation of the SMAD effectors may be blocked by kinase inhibitors (5). (6-7) Persistence of BMP signaling may be modulated by regulating the SMURF1-mediated ubiquitination of SMAD effector proteins by disrupting SMURF1 interaction with SMADs by small molecule inhibitors (6) or by increasing SMURF1 protein levels (7). (8-9) BMP pathway component expression may be elevated by increasing transcription or alleviating microRNA-mediated translational silencing (8). Alternatively, BMP pathway component levels may be reduced by reducing transcription and/or translation rates (9).
Mentions: In this section, we highlight several strategies to activate the BMP pathway. These different approaches are schematized in Figure 1.

Bottom Line: In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling.We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation.We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.

View Article: PubMed Central - PubMed

Affiliation: Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, USA.

ABSTRACT
Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the TGF-β family of ligands and are unequivocally involved in regulating stem cell behavior. Appropriate regulation of canonical BMP signaling is critical for the development and homeostasis of numerous human organ systems, as aberrations in the BMP pathway or its regulation are increasingly associated with diverse human pathologies. In this review, we provide a wide-perspective on strategies that increase or decrease BMP signaling. We briefly outline the current FDA-approved approaches, highlight emerging next-generation technologies, and postulate prospective avenues for future investigation. We also detail how activating other pathways may indirectly modulate BMP signaling, with a particular emphasis on the relationship between the BMP and Activin/TGF-β pathways.

No MeSH data available.


Related in: MedlinePlus