TY - JOUR
T1 - PKR plays a positive role in osteoblast differentiation by regulating GSK-3β activity through a β-catenin-independent pathway
AU - Yoshida, Kaya
AU - Okamura, Hirohiko
AU - Ochiai, Kazuhiko
AU - Hoshino, Yumi
AU - Haneji, Tatsuji
AU - Yoshioka, Masami
AU - Hinode, Daisuke
AU - Yoshida, Hideo
PY - 2012/9/25
Y1 - 2012/9/25
N2 - Double-stranded RNA-dependent protein kinase (PKR) is involved in various cellular functions. We previously reported that PKR regulates osteoblast differentiation, but the specific mechanisms by which this occurs remain unclear. In this study, we investigated the role of PKR in Glycogen synthase kinase 3β (GSK-3β) regulation of osteoblast differentiation. Lithium chloride (LiCl), a GSK-3β inhibitor, increased GSK-3β phosphorylation in MC3T3-E1 and MG-63 cells. LiCl also inhibited Runx2 and expression of its regulated genes, causing inhibition of Alkaline phosphatase activity and mineralization. LiCl injection to the calvaria in mice suppressed bone formation. Further, GSK-3β phosphorylation was increased in osteoblasts, by Akt-independent mechanisms, in which PKR was constitutively inactivated. A PKR inhibitor, 2-aminopurine, also induced GSK-3β phosphorylation in MC3T3-E1 and MG-63 cells. Further, Runx2 and its regulated genes were inhibited in PKR-inactivated osteoblasts, and differentiation was suppressed through a β-catenin-independent pathway. PKR positively regulates the differentiation of osteoblasts by mediating GSK-3β activity through a β-catenin-independent pathway.
AB - Double-stranded RNA-dependent protein kinase (PKR) is involved in various cellular functions. We previously reported that PKR regulates osteoblast differentiation, but the specific mechanisms by which this occurs remain unclear. In this study, we investigated the role of PKR in Glycogen synthase kinase 3β (GSK-3β) regulation of osteoblast differentiation. Lithium chloride (LiCl), a GSK-3β inhibitor, increased GSK-3β phosphorylation in MC3T3-E1 and MG-63 cells. LiCl also inhibited Runx2 and expression of its regulated genes, causing inhibition of Alkaline phosphatase activity and mineralization. LiCl injection to the calvaria in mice suppressed bone formation. Further, GSK-3β phosphorylation was increased in osteoblasts, by Akt-independent mechanisms, in which PKR was constitutively inactivated. A PKR inhibitor, 2-aminopurine, also induced GSK-3β phosphorylation in MC3T3-E1 and MG-63 cells. Further, Runx2 and its regulated genes were inhibited in PKR-inactivated osteoblasts, and differentiation was suppressed through a β-catenin-independent pathway. PKR positively regulates the differentiation of osteoblasts by mediating GSK-3β activity through a β-catenin-independent pathway.
KW - Double-stranded RNA-dependent protein kinase
KW - Glycogen synthase kinase 3β
KW - Osteoblast differentiation
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UR - http://www.scopus.com/inward/citedby.url?scp=84864327531&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2012.03.019
DO - 10.1016/j.mce.2012.03.019
M3 - Article
C2 - 22484461
AN - SCOPUS:84864327531
VL - 361
SP - 99
EP - 105
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
IS - 1-2
ER -