This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.
Date of Award
Doctor of Philosophy (PhD)
Mitochondria exist in a highly dynamic network in many cell types, and mutations in mitochondrial transmembrane GTPase mitofusin2 (MFN2), a key factor that mediates mitochondrial tethering, cause defects in the nervous system. Intriguingly, the skeleton has been overlooked in patients with such mutations. Because expression of MFN2 and its homolog, mitofusin1 (MFN1) increase with maturation of osteoclasts (OCs), which are rich in mitochondria, we sought to determine the role of mitofusins in the OC lineage. Double knockout of Mfn1 and Mfn2 in OC precursors by Lysozyme-M cre reveals that mitofusin activity is required for OC function and maintenance of bone mass in female mice in vivo. In vitro, double knockout bone marrow macrophages are unable to differentiate into mature OCs. Here, OC formation in dcKO BMMs is restored when Mfn2 but not Mfn1 is retrovirally overexpressed. To further explore the role of MFN2 in the OC lineage, we conditionally deleted Mfn2 with LysM-cre and find bone mass is increased in aged female Mfn2 cKOs compared to cre-only littermates. Challenging these single MFN2 knock out animals with acute RANKL injection indicates that Mfn2 is important in female, but not male, OCs, because female Mfn2 cKOs are protected from bone loss with this osteolytic stimuli. Specific MFN2 functions were further assessed in culture. While a MFN2 mutant defective in mitophagy is able to promote osteoclastogenesis, another unable to tether mitochondria is not. This suggests that tethering of mitochondria to eachother and/or the ER by MFN2 is required for osteoclast differentiation, at least in culture. Taken together, our results reveal a sexually divergent role of MFN2-mediated control of mitochondrial dynamics in OC biology. Given the differences in female mice, there may be therapeutic potential to target MFN2 activity for treatment of postmenopausal osteoporosis.
Chair and Committee
Deborah J. Veis Gabriel Mbalaviele
Gerald W. Dorn, II, Roberta Faccio, Jason M. Held,
Ballard, Anna, "The Role of Mitofusins in the Osteoclast Lineage" (2019). Arts & Sciences Electronic Theses and Dissertations. 1882.
Available for download on Sunday, August 01, 2021