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Bone Generation through Mechanical Loading

Authors: R. S. A. Nesbitt, J. Macione, A. Debroy, S. P. Kotha


Bones are dynamic and responsive organs, they regulate their strength and mass according to the loads which they are subjected. Because, the Wnt/β-catenin pathway has profound effects on the regulation of bone mass, we hypothesized that mechanical loading of bone cells stimulates Wnt/β-catenin signaling, which results in the generation of new bone mass. Mechanical loading triggers the secretion of the Wnt molecule, which after binding to transmembrane proteins, causes GSK-3β (Glycogen synthase kinase 3 beta) to cease the phosphorylation of β-catenin. β-catenin accumulation in the cytoplasm, followed by its transport into the nucleus, binding to transcription factors (TCF/LEF) that initiate transcription of genes related to bone formation. To test this hypothesis, we used TOPGAL (Tcf Optimal Promoter β-galactosidase) mice in an experiment in which cyclic loads were applied to the forearm. TOPGAL mice are reporters for cells effected by the Wnt/β-catenin signaling pathway. TOPGAL mice are genetically engineered mice in which transcriptional activation of β- catenin, results in the production of an enzyme, β-galactosidase. The presence of this enzyme allows us to localize transcriptional activation of β-catenin to individual cells, thereby, allowing us to quantify the effects that mechanical loading has on the Wnt/β-catenin pathway and new bone formation. The ulnae of loaded TOPGAL mice were excised and transverse slices along different parts of the ulnar shaft were assayed for the presence of β-galactosidase. Our results indicate that loading increases β-catenin transcriptional activity in regions where this pathway is already primed (i.e. where basal activity is already higher) in a load magnitude dependent manner. Further experiments are needed to determine the temporal and spatial activation of this signaling in relation to bone formation.

Keywords: Bone Resorption and Formation, Mechanical Loading of Bone, Wnt Signaling Pathway & β-catenin

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