Commenced in January 2007
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Edition: International
Paper Count: 30184
Bone Generation through Mechanical Loading

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

Abstract:

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.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1329024

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References:


[1] Robinson, J.A., et al., WNT/beta -catenin signaling is a normal physiological response to mechanical loading in bone. J Biol Chem, 2006.
[2] Balemans W., Van Hul W., Endocrinology 2007, 148, (6), 2622-9.
[3] Sawakami K., Robling A.G., et al., J Biol Chem 2006, 281, (33), 23698-711.
[4] Norvell, S.M., et al., Fluid shear stress induces beta-catenin signaling in osteoblasts. Calcif Tissue Int, 2004. 75(5): p. 396-404.
[5] Gordon, M.D. and R. Nusse, Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem, 2006. 281(32): p. 22429-33.
[6] Is Wnt signalling the final common pathway leading to bone formation? Milat, F., Ng, K.W. 2009 Molecular and Cellular Endocrinology 310 (1-2), pp. 52-62.
[7] Wnt signaling is essential for bone regeneration. Kim, J.B., Leucht, P., Lam, K., Luppen, C.A., ten Berg, D., Nusse, R., Helms, J.A. 2006 MCB Molecular and Cellular Biomechanics 3 (4), pp. 201
[8] Characterization of a transient TCF/LEF-responsive progenitor population in the embryonic mouse retina. Fuhrmann, S., Riesenberg, A.N., Mathiesen, A.M., Brown, E.C., Vetter, M.L., Brown, N.L. 2009 Investigative ophthalmology & visual science 50 (1), pp. 432-440