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.
Recommended Citation
Jules, Joel, "In vitro elucidation of the role and mechanism of RANKL in TNF-and IL-1-mediated osteoclast formation and function" (2010). All ETDs from UAB. 2086.
https://digitalcommons.library.uab.edu/etd-collection/2086