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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