Date of Award

Winter 12-2020

Degree Type

Dissertation

Degree Name

PhD Molecular Bioscience

Department

Biology

Advisor

Jessica Cottrell, Ph.D.

Committee Member

Kyle Kolaja, Ph.D.

Committee Member

James Patrick O'Connor, Ph.D.

Committee Member

Allan Blake, Ph.D.

Committee Member

Constantine Bitsaktsis, Ph.D.

Keywords

myeloma, bone, osteoblast, osteoclast, lesion, remodeling

Abstract

Multiple myeloma (MM) is a hematologic cancer caused by a mature B cell neoplasm, or plasmacytoma, that infiltrates the skeleton at several sites. The disease is characterized by uninhibited transformed plasma cell proliferation that disrupts skeletal homeostasis leading to decreased bone modeling and increased bone resorption. Osteolytic lesions (OL) or voids left in the bone, remain long after the treatment of the cancer and indicate disease progression to myeloma bone disease (MBD). Current combinatorial MM therapies inhibit malignant plasma cell proliferation, slow the progression towards MBD, and increase the mean five-year survival rate, but do little to improve osteoblastic function and restore skeletal homeostasis. Conversely, several novel MBD treatments have been developed to heal OLs, including monoclonal antibodies that target receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin.

A functional in vitro three-dimensional (3D) microphysiological human MM bone model was developed to aid in the identification of improved combinatorial treatments that suppress plasma cell proliferation while healing osteolytic lesions. Bone Marrow Stromal Cell-derived (BMSC) osteoblasts and Bone Marrow macrophage-derived osteoclasts maintained as a homeostatic coculture capable of bone formation and resorption form mineralized bone fragments. The introduction of human plasmacytoma cell lines induce lesions in the Mini-bones decreasing the cumulative hydroxyapatite (HA) content while increasing resorption markers, like C-Terminal Telopeptides Type Collagen 1 (CTX-1) recapitulating physiological conditions of MBD. 3D myeloma disease-induced bone fragments treated with a combination of immunomodulatory and bone modifying agents had lower free CTX-1 and more HA present after twelve days of exposure. These alterations in bone integrity and resorption were dose-dependent and demonstrated the model’s potential to evaluate novel combinatorial therapies.

Download

Share

COinS