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Wnt/β-catenin Signaling Mediates HDAC Inhibitor-induced Osteoblast Differentiation : 히스톤탈아세틸화효소 저해제의 조골세포 분화 촉진 기전 연구

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치의학대학원 치의과학과
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서울대학교 대학원
histone deacetylase inhibitorosteogenic differentiationWnt10Aβ-cateninSmurf1
학위논문 (석사)-- 서울대학교 대학원 : 치의과학과, 2017. 2. 백정화.
Histone deacetylase inhibitors (HDIs) influence a broad repertoire of
biological processes, including cellular proliferation, differentiation, and cell
death, via inhibiting the acetylation of both histone and non-histone proteins.
Currently, HDIs are used as anti-cancer and anti-epileptic drug
positive effects for bone regeneration have recently been reported.
Mechanisms by which HDIs are believed to stimulate osteoblast
differentiation include the acetylation of Runx2 and osterix
however, a further
understanding of additional mechanisms is needed. In this study, to
investigate additional mechanisms of HDIs in osteoblast differentiation, it was
examined the role of Wnt/β-catenin signaling, one of the key positive signaling pathways for osteoblast differentiation, and Smurf1 expression as
a negative regulator of osteoblast differentiation in response to HDIs. To this
end, we used trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA),
and MS275 as HDIs, along with cultured C2C12 cells and primary cultured
mouse calvarial cells (MC cells). To elucidate the effects of HDIs on
osteoblast differentiation, C2C12 cells were incubated with HDIs and a sub
minimal concentration of bone morphogenetic protein 2 (BMP2, 10 ng/mL)
followed by alkaline phosphatase (ALP) staining, ALP activity assays, and
quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for
bone marker genes. C2C12 cells were treated with only HDIs for select parts
of the experiment to verify the molecular mechanisms of HDIs. Experimental
results demonstrated that C2C12 cells differentiated into osteoblasts when
incubated with HDIs and BMP2, but not when treated with BMP2 alone. HDIs
activated Wnt/β-catenin signaling, with HDIs inducing the Wnt10A gene to
the highest extent. In addition, HDIs repressed Smurf1 expression and these
effects were dependent on Wnt/β-catenin signaling. Taken together, these
results suggest that HDIs enhance osteoblast differentiation through the
increased expression of Wnt10A and the activation of Wnt/β-catenin
signaling and subsequent decrease in Smurf1 expression.
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