Browsing by Subject "Transcriptional regulation"

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    Involvement of Histone Deacetylase 4 (HDAC4) in Osteoclast Function
    (2019-08) Faulkner, Bora
    Bone modeling and remodeling during development and bone integrity throughout life are normally regulated via complex coupled actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Loss of coupling between bone formation and bone resorption leads to pathogenesis of bone metabolic diseases including osteoporosis or osteopetrosis. Defects in osteoclast activity, whether increased activity or deficiency is responsible for bone destruction in many bone diseases such as osteoporosis, osteopetrosis and rheumatoid arthritis rather than impaired osteoblastic bone formation. Despite our growing knowledge in the mechanisms involved in the regulation of osteoclast differentiation and function, there is still a lot unknown. For this reason, it is important to understand the molecular mechanisms underlying how the activity of these bone-resorbing cells are regulated in order to develop effective therapies for bone disorders. Histone deacetylation is one such potential mechanism. It has been reported that class IIa histone deacetylase (HDAC), which include HDAC4, 5, 7 and 9 are regulators of osteoclastogenesis. Evidence from our lab and other labs using in vitro cell culture and in vivo mouse model systems indicated that HDAC7 and 9 are negative regulators of osteoclast differentiation and activity. However, whether the other class IIa members are functionally significant in osteoclasts is largely unknown. The aim of this research was to use in vitro osteoclast cell culture assays in conjunction with an in vivo mouse model to investigate the role(s) of HDAC4 in osteoclasts. HDAC4 conditional knockout (4cKO) mice exhibited increased bone mass phenotype (osteopetrosis) cause by decreased bone-resorbing activity of osteoclasts. HDAC4-deficient osteoclasts show reduced resorptive activity resulting from impaired signaling downstream of the M-CSF and v3 integrin and diminished M-CSF mediated adhesion and migration. Moreover, I demonstrated that c-Src activation in osteoclasts is regulated by HDAC4. The results of this thesis have identified HDAC4 as an essential regulator of osteoclast bone resorption activity both in vivo and in vitro.