TY - JOUR
T1 - Bone morphogenetic protein 9 (BMP9) directly induces Notch effector molecule Hes1 through the SMAD signaling pathway in osteoblasts
AU - Seong, Chang Hwan
AU - Chiba, Norika
AU - Kusuyama, Joji
AU - Subhan Amir, Muhammad
AU - Eiraku, Nahoko
AU - Yamashita, Sachiko
AU - Ohnishi, Tomokazu
AU - Nakamura, Norifumi
AU - Matsuguchi, Tetsuya
N1 - Funding Information:
We thank Ms. Yoko Amita and Ms. Tomomi Fujii for the secretarial assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology.
Publisher Copyright:
© 2020 Federation of European Biochemical Societies
PY - 2021/2
Y1 - 2021/2
N2 - Bone morphogenetic protein (BMP) 9 is one of the most osteogenic BMPs, but its mechanism of action has not been fully elucidated. Hes1, a transcriptional regulator with a basic helix-loop-helix domain, is a well-known effector of Notch signaling. Here, we find that BMP9 induces periodic increases of Hes1 mRNA and protein expression in osteoblasts, presumably through an autocrine negative feedback mechanism. BMP9-mediated Hes1 induction is significantly inhibited by an ALK inhibitor and overexpression of Smad7, an inhibitory Smad. Luciferase and ChIP assays revealed that two Smad-binding sites in the 5′ upstream region of the mouse Hes1 gene are essential for transcriptional activation by BMP9. Thus, our data indicate that BMP9 induces Hes1 expression in osteoblasts via the Smad signaling pathway.
AB - Bone morphogenetic protein (BMP) 9 is one of the most osteogenic BMPs, but its mechanism of action has not been fully elucidated. Hes1, a transcriptional regulator with a basic helix-loop-helix domain, is a well-known effector of Notch signaling. Here, we find that BMP9 induces periodic increases of Hes1 mRNA and protein expression in osteoblasts, presumably through an autocrine negative feedback mechanism. BMP9-mediated Hes1 induction is significantly inhibited by an ALK inhibitor and overexpression of Smad7, an inhibitory Smad. Luciferase and ChIP assays revealed that two Smad-binding sites in the 5′ upstream region of the mouse Hes1 gene are essential for transcriptional activation by BMP9. Thus, our data indicate that BMP9 induces Hes1 expression in osteoblasts via the Smad signaling pathway.
KW - Bone Morphogenetic Protein 9
KW - Hes1
KW - bone regeneration
KW - notch
KW - osteogenic differentiation
UR - http://www.scopus.com/inward/record.url?scp=85098095748&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098095748&partnerID=8YFLogxK
U2 - 10.1002/1873-3468.14016
DO - 10.1002/1873-3468.14016
M3 - Article
C2 - 33264418
AN - SCOPUS:85098095748
SN - 0014-5793
VL - 595
SP - 389
EP - 403
JO - FEBS Letters
JF - FEBS Letters
IS - 3
ER -