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The Divergent Effects of Parathyroid Hormone Regulated Wnt-4 in Osteoblasts and Mouse Bone Marrow

by
Marika K. Bergenstock
B.A./B.S., 2002
University of Rochester

Thesis Advisor: Nicola C. Partridge, Ph.D.

Graduate Program in Biomedical Engineering

SPH/Research Building
Room 258

Monday, September 22, 2008
10:00 am


Abstract

Parathyroid hormone (PTH) can activate multiple signaling pathways after binding to its seven-transmembrane receptor, parathyroid hormone-1 (PTHR1), which is found on osteoblasts. PTH increases bone formation by directing changes in osteoblast function and acts as either a catabolic or an anabolic factor in bone, depending on its method of administration. As a result of its anabolic effect, PTH is the only clinically available anabolic agent used for treating osteoporosis.

Microarray data have shown that PTH regulates molecules of the Wnt signaling family in bone and osteoblastic cells. Wnt proteins are essential in development and are active in bone forming processes. We discovered that non-canonical Wnt-4 is PTH-regulated and expressed by bone lining cells and hypertrophic chondrocytes after PTH stimulation. We further describe WNT-4s exogenous ability to enhance osteoblast differentiation through activation of Wnt/Ca2+ and Wnt/PCP non-canonical signaling pathways. This research is of importance to the bone field since non-canonical Wnt signaling pathways have not been sufficiently investigated in bone maintenance or as contributing to PTHs anabolic effects in bone.

Hematopoietic and mesenchymal stem cell lineages reside in bone and have been shown to be targets of Wnt proteins and their signaling pathways. We furthered our understanding of WNT-4s role in the bone environment by investigating WNT-4 treated mouse bone marrow stromal stem cells (mBMSSCs). Here we identified that WNT-4 stimulates mBMSSC proliferation by inhibiting apoptosis. Most significantly, WNT-4 was determined to have differential effects on mBMSSCs depending on their developmental stage. WNT-4 activates canonical Wnt/beta-catenin signaling in proliferating mBMSSCs. In differentiating mBMSSCs, WNT-4 activates non-canonical Wnt signaling pathways and enhances osteoblast differentiation while inhibiting adipocyte differentiation.

We have demonstrated that canonical Wnt proteins are not exclusively important in bone. Ultimately, since Wnt-4 is PTH-regulated in bone, we provide further information for understanding the mechanism behind PTHs dual effects in this environment.


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