Date of Award

2019

Embargo Period

6-24-2024

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Pathology and Laboratory Medicine

College

College of Graduate Studies

First Advisor

Amanda C. LaRue

Second Advisor

James J. Cray

Third Advisor

Victoria J. Findlay

Fourth Advisor

Meenal Mehrotra

Fifth Advisor

Robin Muise-Helmericks

Sixth Advisor

Vincent D. Pellegrini

Abstract

Musculoskeletal extremity injuries are a major cause of morbidity in US populations, including Veterans and seniors. Long bone fracture repair requires osteogenic progenitor cells capable of producing mature osteocytes that supply the cellular and granular components of remodeling bone. Our previously published work demonstrates that murine hematopoietic stem cells (HSC) are a novel source of osteogenic progenitor cells. Early studies demonstrated the osteogenic potential of human bone marrow-derived adherent cells in vitro and implicated IGF2 as a novel pro-osteogenic factor in these cells, through activation of endogenous phosphatase SHP2. Building on this foundation, I hypothesized that human HSC-derived osteogenic progenitor cells are capable of differentiating into mature osteocytes, participating in fracture repair, and that SHP2 inhibition would prevent IGF-mediated potentiation of osteoblastic differentiation. I demonstrate the osteogenic capacity of HSCs by immunohistochemical evidence of human-derived osteocytes in mice. In vitro studies demonstrated enhanced mineralization of human bone marrow-derived adherent cells treated with IGF2. This enhanced mineralization was secondary to IGF2-induced activation of mitogenic AKT and ERK signaling. The enhanced mineralization after IGF2 treatment required SHP2 function. Genetic and pharmacological SHP2 inhibition reduced osteoblastic mineralization in vitro. These studies underscore the need to evaluate the effect of SHP2 inhibition on skeletal health as targeted SHP2 inhibitors enter clinical practice.

Rights

All rights reserved. Copyright is held by the author.

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