Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability Through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells

Yeonsil Yu; Se Young Oh; Ha Yeong Kim; Ji Young Choi; Sangmee Ahn Jo; Inho Jo

doi:10.3390/cells11030534

Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability Through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells

Yeonsil Yu, Se Young Oh, Ha Yeong Kim, Ji Young Choi, Sangmee Ahn Jo, Inho Jo

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1–5 mM), a well-known histone deacetylase (HDAC) inhibitor, strongly inhibited TMSC proliferation without altering MSC-specific surface markers, CD14, 34, 45, 73, 90 and 105. However, CD146 expression increased at 5 mM VPA. VPA increased osteogenic differentiation of TMSCs but decreased adipogenesis and chondrogenesis, as evidenced by the cell-specific staining of differentiation. The former was validated by the increased osteocalcin (OCN). The changes in CCN1 by VPA was biphasic; it increased until 48 h and decreased thereafter. Knockdown of CCN1 by using siRNA inhibited the osteogenic effect of VPA. VPA had no effect on CCN1 mRNA expres-sion, but inhibition of protein synthesis by cycloheximide showed that VPA slowed down the CCN1 protein degradation. Moreover, overexpression of HDAC1 completely inhibited VPA-induced CCN1. Our results indicate that VPA inhibits the HDAC1, inducing CCN1 protein stability rather than gene expression, thereby promoting osteogenic differentiation of TMSCs. These findings pre-sent the noble implication of VPA as an inhibitor of HDAC1 to facilitate CCN1-induced osteogenic differentiation of MSCs.

Original language	English
Article number	534
Journal	Cells
Volume	11
Issue number	3
DOIs	https://doi.org/10.3390/cells11030534
State	Published - 1 Feb 2022

Keywords

CCN1
Osteogenesis
Tonsil-derived mesenchymal stem cells (TMSCs)
Valproic acid (VPA)

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10.3390/cells11030534

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title = "Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability Through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells",

abstract = "Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1–5 mM), a well-known histone deacetylase (HDAC) inhibitor, strongly inhibited TMSC proliferation without altering MSC-specific surface markers, CD14, 34, 45, 73, 90 and 105. However, CD146 expression increased at 5 mM VPA. VPA increased osteogenic differentiation of TMSCs but decreased adipogenesis and chondrogenesis, as evidenced by the cell-specific staining of differentiation. The former was validated by the increased osteocalcin (OCN). The changes in CCN1 by VPA was biphasic; it increased until 48 h and decreased thereafter. Knockdown of CCN1 by using siRNA inhibited the osteogenic effect of VPA. VPA had no effect on CCN1 mRNA expres-sion, but inhibition of protein synthesis by cycloheximide showed that VPA slowed down the CCN1 protein degradation. Moreover, overexpression of HDAC1 completely inhibited VPA-induced CCN1. Our results indicate that VPA inhibits the HDAC1, inducing CCN1 protein stability rather than gene expression, thereby promoting osteogenic differentiation of TMSCs. These findings pre-sent the noble implication of VPA as an inhibitor of HDAC1 to facilitate CCN1-induced osteogenic differentiation of MSCs.",

keywords = "CCN1, Osteogenesis, Tonsil-derived mesenchymal stem cells (TMSCs), Valproic acid (VPA)",

author = "Yeonsil Yu and Oh, {Se Young} and Kim, {Ha Yeong} and Choi, {Ji Young} and Jo, {Sangmee Ahn} and Inho Jo",

note = "Funding Information: Author Contributions: Conceptualization, Y.Y., S.A.J. and I.J.; methodology, Y.Y., J.-Y.C. and I.J.; software, Y.Y., S. -Y.O. and H.Y.K.; validation, Y.Y., S.-Y.O. and H.Y.K.; formal analysis, Y.Y., H.Y.K. and J.-Y.C.; investigation, Y.Y., H.Y.K. and J. -Y.C.; resources, Y.Y., S.-Y.O., S.A.J. and I.J.; data curation, Y.Y., S.-Y.O. and I.J.; writing—original draft preparation, Y.Y., S.-Y.O. and I.J.; writing—review and editing, S.-Y.O., S.A.J. and I.J.; visualization, Y.Y., S.-Y.O. and H.Y.K.; supervision, S.A.J. and I.J.; project administration, Y.Y., S.A.J. and I.J.; funding acquisition, Y.Y., S.-Y.O., S.A.J. and I.J. All authors have read and agreed to the published version of the manuscript Funding: This work was financially supported by the Basic Science Research (2017M3A9B3063636, 2019R1A2C1086767) and Creative and Exploratory Research (2021R1I1A1A01046931) programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning. The paper was also supported by the RP-Grant 2020. Publisher Copyright: {\textcopyright} 2022 by the authors. Li-censee MDPI, Basel, Switzerland.",

year = "2022",

month = feb,

day = "1",

doi = "10.3390/cells11030534",

language = "English",

volume = "11",

journal = "Cells",

issn = "2073-4409",

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TY - JOUR

T1 - Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability Through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells

AU - Yu, Yeonsil

AU - Oh, Se Young

AU - Kim, Ha Yeong

AU - Choi, Ji Young

AU - Jo, Sangmee Ahn

AU - Jo, Inho

N1 - Funding Information: Author Contributions: Conceptualization, Y.Y., S.A.J. and I.J.; methodology, Y.Y., J.-Y.C. and I.J.; software, Y.Y., S. -Y.O. and H.Y.K.; validation, Y.Y., S.-Y.O. and H.Y.K.; formal analysis, Y.Y., H.Y.K. and J.-Y.C.; investigation, Y.Y., H.Y.K. and J. -Y.C.; resources, Y.Y., S.-Y.O., S.A.J. and I.J.; data curation, Y.Y., S.-Y.O. and I.J.; writing—original draft preparation, Y.Y., S.-Y.O. and I.J.; writing—review and editing, S.-Y.O., S.A.J. and I.J.; visualization, Y.Y., S.-Y.O. and H.Y.K.; supervision, S.A.J. and I.J.; project administration, Y.Y., S.A.J. and I.J.; funding acquisition, Y.Y., S.-Y.O., S.A.J. and I.J. All authors have read and agreed to the published version of the manuscript Funding: This work was financially supported by the Basic Science Research (2017M3A9B3063636, 2019R1A2C1086767) and Creative and Exploratory Research (2021R1I1A1A01046931) programs through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning. The paper was also supported by the RP-Grant 2020. Publisher Copyright: © 2022 by the authors. Li-censee MDPI, Basel, Switzerland.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1–5 mM), a well-known histone deacetylase (HDAC) inhibitor, strongly inhibited TMSC proliferation without altering MSC-specific surface markers, CD14, 34, 45, 73, 90 and 105. However, CD146 expression increased at 5 mM VPA. VPA increased osteogenic differentiation of TMSCs but decreased adipogenesis and chondrogenesis, as evidenced by the cell-specific staining of differentiation. The former was validated by the increased osteocalcin (OCN). The changes in CCN1 by VPA was biphasic; it increased until 48 h and decreased thereafter. Knockdown of CCN1 by using siRNA inhibited the osteogenic effect of VPA. VPA had no effect on CCN1 mRNA expres-sion, but inhibition of protein synthesis by cycloheximide showed that VPA slowed down the CCN1 protein degradation. Moreover, overexpression of HDAC1 completely inhibited VPA-induced CCN1. Our results indicate that VPA inhibits the HDAC1, inducing CCN1 protein stability rather than gene expression, thereby promoting osteogenic differentiation of TMSCs. These findings pre-sent the noble implication of VPA as an inhibitor of HDAC1 to facilitate CCN1-induced osteogenic differentiation of MSCs.

AB - Our previous study found that the level of CCN1 increases as osteogenic differentiation progresses in tonsil-derived mesenchymal stem cells (TMSCs). This study investigated how CCN1 is regulated through HDAC inhibition in TMSCs and their relationship with osteogenesis. Valproic acid (VPA) (1–5 mM), a well-known histone deacetylase (HDAC) inhibitor, strongly inhibited TMSC proliferation without altering MSC-specific surface markers, CD14, 34, 45, 73, 90 and 105. However, CD146 expression increased at 5 mM VPA. VPA increased osteogenic differentiation of TMSCs but decreased adipogenesis and chondrogenesis, as evidenced by the cell-specific staining of differentiation. The former was validated by the increased osteocalcin (OCN). The changes in CCN1 by VPA was biphasic; it increased until 48 h and decreased thereafter. Knockdown of CCN1 by using siRNA inhibited the osteogenic effect of VPA. VPA had no effect on CCN1 mRNA expres-sion, but inhibition of protein synthesis by cycloheximide showed that VPA slowed down the CCN1 protein degradation. Moreover, overexpression of HDAC1 completely inhibited VPA-induced CCN1. Our results indicate that VPA inhibits the HDAC1, inducing CCN1 protein stability rather than gene expression, thereby promoting osteogenic differentiation of TMSCs. These findings pre-sent the noble implication of VPA as an inhibitor of HDAC1 to facilitate CCN1-induced osteogenic differentiation of MSCs.

KW - CCN1

KW - Osteogenesis

KW - Tonsil-derived mesenchymal stem cells (TMSCs)

KW - Valproic acid (VPA)

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U2 - 10.3390/cells11030534

DO - 10.3390/cells11030534

M3 - Article

C2 - 35159343

AN - SCOPUS:85123887113

SN - 2073-4409

VL - 11

JO - Cells

JF - Cells

IS - 3

M1 - 534

ER -

Valproic Acid-Induced CCN1 Promotes Osteogenic Differentiation by Increasing CCN1 Protein Stability Through HDAC1 Inhibition in Tonsil-Derived Mesenchymal Stem Cells

Abstract

Keywords

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