miR-155 modulates TNF-α-inhibited osteogenic differentiation by targeting SOCS1 expression.
Bone morphogenetic proteins (BMPs) can induce ectopic bone formation, which is negatively regulated by inflammatory cytokines, such as tumor necrosis factor (TNF)-α. Recently, miR-155 has been reported to regulate the transforming growth factor (TGF)-β signaling pathway and inflammatory responses. However, whether and how miR-155 modulates TNF-α-regulated osteogenic differentiation have not been explored. In this study, we demonstrated that miR-155 was involved in TNF-α-mediated inhibition of osteogenic differentiation. Knockdown of miR-155 partially mitigated the inhibition of TNF-α on BMP-2-induced osteogenic differentiation. Bioinformatic analysis identified the candidate target site in the 3' untranslated region (3'UTR) of SOCS1. Knockdown of miR-155 increased SOCS1 protein expression during TNF-α stimulation in MC3T3-E1 cells. And transfection with miR-155 inhibited the wild-type, but not the mutant, 3'UTR of SOCS1-regulated luciferase activity, indicating that SOCS1 is a direct target of miR-155 in osteoblast cells. Furthermore, miR-155 expression could be induced by TNF-α through the JNK pathway. As the result of increased SOCS1 expression, knockdown of miR-155 significantly reduced the JNK/c-Jun activation. In addition, transfection of SOCS1 siRNA or overexpression of SOCS1 coding region could narrow the differences of alkaline phosphatase (ALP) and osteocalcin (OSC) expression between the control and miR-155 inhibitor transfected cells. These data indicated that miR-155 modulates TNF-α-regulated osteogenic differentiation by targeting SOCS1, at least partially through the SAPK/JNK pathway. These findings may provide new insights into understanding the regulatory role of miR-155 in the process of osteogenic differentiation in inflammatory condition.
Department of Prosthodontics, Shanghai Key Laboratory of Stomatology, Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Tingting
T
Wu
Ming
M
Xie
Xiaojie
X
Wang
Xinquan
X
Jiang
Jing
J
Li
Hui
H
Huang
D000818:Animals; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D016366:Open Reading Frames / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D055396:Bone Morphogenetic Protein 2; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha