Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

January 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Yousef Abu-Amer

Abstract

Bone homeostasis is essential for health and is altered in many pathological conditions. A balance in the activity of osteoblasts: bone-building cells) and osteoclasts: boneresorbing cells) determines the state of bone metabolism, and a tip in this balance toward either cell type is detrimental to health. In clinical settings, the most common bone diseases favor increased osteoclast activity and include osteoporosis and rheumatoid arthritis. Heightened osteoclast differentiation and activation in these conditions causes bone loss which results in increased fracture risk, bone pain, and deformity. Understanding the mechanisms by which osteoclasts develop will elucidate important targets for therapy in these conditions. Osteoclasts differentiate from monocyte precursors when stimulated by the Ligand for Receptor Activator of NF-κB: RANKL). Recent research has identified many transcription factors that are activated by RANKL and are important for osteoclast differentiation. One such family of transcription factors is NF-κB. We hypothesized that activators of NF-κB are necessary for RANKL-induced osteoclast differentiation. The Inhibitory kappaB Kinase: IKK) Complex, which consists of two catalytically active subunits, IKKα and IKKβ, and one regulatory subunit, NEMO, is the main stimulator of NF-κB downstream of RANK in osteoclast progenitors. Our lab and others show that this activation is critical for stimulation of NF-κB and osteoclastogenesis. We sought to further characterize the role of the IKK complex in osteoclastogenesis by conditionally deleting IKKβ from osteoclast precursors. Using this mouse model, we demonstrated that IKKβ is critical for differentiation of osteoclasts in vivo and in vitro, and that IKKβ supports osteoclastogenesis at the levels of differentiation and survival. Our model provided a useful tool to study the structural components of IKKβ which are important for its function in osteoclast differentiation. Retroviral rescue experiments in which IKKβ KO monocytes were reconstituted with mutant forms of IKKβ revealed that activation loop serines are critical for IKKβ to support osteoclast differentiation. These experiments led to the discovery that constitutive activation of IKKβ results in spontaneous, RANK-independent osteoclast differentiation in vitro and osteolysis in vivo. Our work demonstrates that IKKβ is central to osteoclast differentiation and is therefore an important target in therapy for osteoclast-mediated disease.

Comments

Permanent URL: http://dx.doi.org/10.7936/K71V5C0M

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