Elucidating the Antagonistic Relationship Between Bone Morphogenetic Proteins and Activins in the Skeleton

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Medicine and Health Sciences


Osteoporosis is a disease that results from changes in bone mineral density (BMD). In the United States, over 10 million people have low BMD and have an increased risk for fractures, hospitalization and mortality. BMD is the sum of bone formation and bone reabsorption. A growing body of evidence indicates that the Bone Morphogenetic Protein (BMP) pathway promotes bone formation through action of the effectors SMAD1, 5, and 8 while the Activin pathway negatively influences bone mass through action of the effectors SMAD2 and 3. Recent studies from our lab suggest that BMP and Activin ligands regulate bone mass in a see-saw-like mechanism via competition for a shared pool of receptors. Design: In the present study we seek to test this hypothesis in vitro via signaling responsiveness assays using pathway-specific transcriptional reporters and western blot. Proof of principle experiments were carried out in the non-skeletal cell line HEK293 and current work utilizes the osteogenic cell line W-20-17. Results: We first used western blots to confirm that HEK293 cells specifically respond to BMP2 and Activin-A treatment by increasing levels of activated SMAD1, 5, and 8 or SMAD2 and 3, respectively. We then performed dose response assays utilizing increasing concentrations of each ligand to identify the ECmin and ECmax for each ligand. These data informed our reporter assays, which were confirmed to be specific to either BMP or Activin pathway activation with no cross-activation observed. Current studies are extending these preliminary findings to W-20-17 cells where we will perform competition assays between BMP and Activin ligands to examine the role of receptor-level competition in determining the ratio of these two pathways. We hope that elucidating the mechanisms that regulate the antagonism between these pathways will identify novel opportunities for safer and more effective therapies to treat low BMD in humans.


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