TY - JOUR
T1 - Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of bone morphogenetic protein-2 and tumor necrosis factor-α in C2C12 cells
AU - Matsumoto, Yoshinori
AU - Otsuka, Fumio
AU - Narazaki, Mariko
AU - Mukai, Tomoyuki
AU - Yamanaka, Ryutaro
AU - Takeda, Masaya
AU - Miyoshi, Tomoko
AU - Inagaki, Kenichi
AU - Sada, Kenei
AU - Makino, Hirofumi
PY - 2010/8
Y1 - 2010/8
N2 - Imbalanced functions between osteoclasts and osteoblasts are involved in inflammatory bone damage. The clinical effectiveness of blocking TNF-α in treatment of active rheumatoid arthritis established the significance of TNF-α in the pathogenesis. In the present study, we investigated the cellular mechanism by which estrogen and glucocorticoid interact in osteoblastic differentiation regulated by BMP and TNF-α using mouse myoblastic C2C12 cells. The expression of estrogen receptors, (ER)α and ERβ, and glucocorticoid receptor (GCR) was significantly increased by BMP-2 treatment regardless of the presence of estradiol and dexamethasone. Estradiol, but not dexamethasone, enhanced BMP-induced Runx2 and osteocalcin expression in C2C12 cells. In addition, TNF-α suppressed BMP-2-induced Runx2 and osteocalcin expression, and estradiol and dexamethasone reversed the TNF-α effects on BMP-2-induced Runx2 expression. Dexamethasone also abolished osteocalcin expression induced by BMP-2. Interestingly, BMP-2-induced Smad1/5/8 phosphorylation and Id-1 promoter activity were enhanced by estradiol pretreatment. On the other hand, dexamethasone suppressed BMP-2-induced Smad1/5/8 activation. TNF-α-induced SAPK/JNK activity was suppressed by estradiol, while NFκB phosphorylation was inhibited by dexamethasone. Of note, the inhibitory effects of TNF-α on BMP-2-induced Runx2 and osteocalcin expression were reversed by SAPK/JNK inhibition regardless of the presence of estradiol. The estradiol effects that enhance BMP-2-induced Runx2 and osteocalcin mRNA expression were restored by antagonizing ER, and moreover, membrane-impermeable estradiol-BSA failed to enhance the BMP-2-induced osteoblastic differentiation. Thus, estrogen and glucocorticoid are functionally involved in the process of osteoblast differentiation regulated by BMPs and TNF-α. BMP-2 increases the sensitivities of ERs and GCR, whereas estrogen and glucocorticoid differentially regulate BMP-Smad and TNF-α signaling.
AB - Imbalanced functions between osteoclasts and osteoblasts are involved in inflammatory bone damage. The clinical effectiveness of blocking TNF-α in treatment of active rheumatoid arthritis established the significance of TNF-α in the pathogenesis. In the present study, we investigated the cellular mechanism by which estrogen and glucocorticoid interact in osteoblastic differentiation regulated by BMP and TNF-α using mouse myoblastic C2C12 cells. The expression of estrogen receptors, (ER)α and ERβ, and glucocorticoid receptor (GCR) was significantly increased by BMP-2 treatment regardless of the presence of estradiol and dexamethasone. Estradiol, but not dexamethasone, enhanced BMP-induced Runx2 and osteocalcin expression in C2C12 cells. In addition, TNF-α suppressed BMP-2-induced Runx2 and osteocalcin expression, and estradiol and dexamethasone reversed the TNF-α effects on BMP-2-induced Runx2 expression. Dexamethasone also abolished osteocalcin expression induced by BMP-2. Interestingly, BMP-2-induced Smad1/5/8 phosphorylation and Id-1 promoter activity were enhanced by estradiol pretreatment. On the other hand, dexamethasone suppressed BMP-2-induced Smad1/5/8 activation. TNF-α-induced SAPK/JNK activity was suppressed by estradiol, while NFκB phosphorylation was inhibited by dexamethasone. Of note, the inhibitory effects of TNF-α on BMP-2-induced Runx2 and osteocalcin expression were reversed by SAPK/JNK inhibition regardless of the presence of estradiol. The estradiol effects that enhance BMP-2-induced Runx2 and osteocalcin mRNA expression were restored by antagonizing ER, and moreover, membrane-impermeable estradiol-BSA failed to enhance the BMP-2-induced osteoblastic differentiation. Thus, estrogen and glucocorticoid are functionally involved in the process of osteoblast differentiation regulated by BMPs and TNF-α. BMP-2 increases the sensitivities of ERs and GCR, whereas estrogen and glucocorticoid differentially regulate BMP-Smad and TNF-α signaling.
KW - Bone morphogenetic protein (BMP)
KW - Estrogen
KW - Estrogen receptor (ER)
KW - Glucocorticoid
KW - Nuclear factor-κB (NFκB)
KW - Tumor necrosis factor-α (TNF-α)
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UR - http://www.scopus.com/inward/citedby.url?scp=77954387472&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2010.05.004
DO - 10.1016/j.mce.2010.05.004
M3 - Article
C2 - 20638987
AN - SCOPUS:77954387472
VL - 325
SP - 118
EP - 127
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
SN - 0303-7207
IS - 1-2
ER -