Indiana University-Purdue University Indianapolis (IUPUI) / The aging US population is experiencing a growing incidence of osteoporosis,
characterized by increased fracture risk and low bone mass. In skeletal tissue, canonical
Wnt signaling is a critical regulator of bone mass, and dysregulation of the Wnt pathway
has been implicated in numerous skeletal displasias. Some components of the Wnt
signaling pathway have a clear role in bone homeostasis, particularly in the response of
bone to altered mechanical environment. Other pathway components are more poorly
defined. One important intracellular signal transduction node in the Wnt cascade is β-
catenin, which modulates gene expression and cell-cell junctions, among other functions.
During periods of disuse, β-catenin is degraded, leading to inhibition of Wnt targets.
Here, I characterize the role of β-catenin in bone during a disuse challenge, using a
genetic mouse model expressing an inducible constitively-active mutant form of β-
catenin in the osteocyte population. I hypothesize that prevention of β-catenin
degradation during disuse will prevent the bone wasting effects of mechanodeprivation.
As a second goal, I focus on upstream (membrane-bound) modulation of Wnt. Here, I
investigate the low-density lipoprotein receptor-related receptor 4 (Lrp4), in the
regulation of bone mass and mechanotransduction. I generated an Lrp4 knockin mouse
model harboring a missense mutation found among human patients with abnormally high
bone mass. I hypothesize that the mutation compromises sclerostin action on bone cells.
Understanding how each of these components of the Wnt signaling pathway interact, may
lead to novel therapeutic targets for treatment of bone diseases.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/21599 |
| Date | 11 1900 |
| Creators | Bullock, Whitney Ann |
| Contributors | Robling, Alexander, Bidwell, Joseph, Plotkin, Lilian, Sankar, Uma, White, Kenneth |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Language | en_US |
| Detected Language | English |
| Type | Dissertation |
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