All ETDs from UAB

Advisory Committee Chair

Xu Feng

Advisory Committee Members

Scott W Ballinger

Amjad Javed

Jay M McDonald

John M Mountz

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The receptor activator of NF-қB (RANK) ligand (RANKL) and its receptor RANK play a critical role in osteoclast biology. RANK has three tumor necrosis factor receptor associated factor (TRAF)-binding motifs [PFQEP369-373 (Motif 1), PVQEET559-564 (Motif 2), and PVQEQG604-609 (Motif 3)] that regulate osteoclast formation and function. RANK also contains a TRAF-independent motif (IVVY535-538) that commits bone marrow macrophages (BMMs), which are osteoclast precursors, to the osteoclast lineage for osteoclastogenesis. Notably, tumor necrosis factor-α (TNF) and interlukin-1 (IL-1) utilize TRAFs to initiate most of the signaling pathways known to be activated by RANKL but fail to form osteoclasts unless attended by permissive levels of RANKL, suggesting that TNF- and IL-1-mediated osteoclastogenesis may require priming of BMMs by RANKL. Moreover, unlike RANK, TNF and IL-1 receptors lack the IVVY motif, which may explain the inability of TNF or IL-1 alone to stimulate osteoclastogenesis. Herein, I sought to determine the molecular mechanism underlying the RANKL requirement for TNF- and IL-1-mediated osteoclast formation and function by using a chimeric-receptor approach. In the first and second parts of my thesis, I addressed the role of the RANK IVVY motif in TNF- and IL-1-mediated osteoclastogenesis, respectively. I then determined the role of Motif 1/Motif 2/Motif 3 of RANK in TNF- and IL-1-mediated osteoclast formation and function. The results indicate that TNF- and IL-1-mediated osteoclastogenesis requires RANK signaling from IVVY motif, Motif 2 and Motif 3. Significantly, my thesis work has established that the RANK IVVY535-538, PVQEET559-564, and PVQEQG604-609 motifs may serve as attractive therapeutic targets for bone loss accompanying many bone disorders.

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