Critical role of the extracellular signal–regulated kinase–MAPK pathway in osteoblast differentiation and skeletal development

Ge, Chunxi; Xiao, Guozhi; Jiang, Di; Franceschi, Renny T.

doi:10.1083/jcb.200610046

Cited by 451 publications

(311 citation statements)

References 53 publications

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“…In the past decade, the role of ERK and p38 in the osteoblastic differentiation of bone marrow-derived stromal cells, calvarial osteoblasts, preosteoblast cell lines, and MSCs have been well studied. (8,19,21,37) Only recently, the role of JNK in osteoblastic differentiation was investigated. BMP2 is a wellknown osteoblastic differentiation inducer characterized by induction of osteoblastic markers.…”

Section: Discussionmentioning

confidence: 99%

“…The roles of ERK and p38 activation in osteoblastic differentiation have been well studied, (17)(18)(19)21) whereas the role of JNK1 activation in osteoblastic differentiation remains to be elucidated. To determine the role of JNK1 in osteoblastic differentiation, C2C12 and MC3T3-E1 cells were treated with BMP2 in the presence and absence of specific JNK inhibitor, SP600125, and two osteoblastic functions, ALP activity and bone mineralization, were compared.…”

Section: Inhibition Of Jnk Activity and Expression Enhances Bmp2-indumentioning

confidence: 99%

“…(8,14,16) For example, both phosphorylation and transcriptional activity of Runx2 can be stimulated by the ERK and p38 pathways. (17)(18)(19)(20)(21)(22) Although the involvements of ERK and p38 pathways in osteoblastic differentiation have been well studied, the phosphorylation and activity of Runx2 modified by JNK during osteoblastic differentiation remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

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c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic proteins 2 (BMP2). Mitogenactivated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other kinase of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first showed that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then showed that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain-offunction, such as enforced expression of a constitutively active JNK1 (CA-JNK1). Most importantly, we showed that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type (WT) Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation. ß

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Section: Discussionmentioning

confidence: 99%

Section: Inhibition Of Jnk Activity and Expression Enhances Bmp2-indumentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

Huang¹,

Lin²,

Chao³

et al. 2012

Journal of Bone and Mineral Research

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“…Osteogenesis, a highly coordinated process, involves transcription factors such as BMP2, RUNX2 and OSTERIX, and drives stem cells to fully differentiated osteocytes 5, 6, 7, 8. Osteogenesis is promoted through several signalling pathways, including WNT/β‐catenin, BMP, JAK/STAT and MAPK 9, 10, 11.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐98 regulates osteogenic differentiation of human bone mesenchymal stromal cells by targeting BMP2

Zhang

Zhu

et al. 2016

J Cellular Molecular Medi

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To study the effects of microRNA‐98 (miR‐98) on human bone mesenchymal stromal cells (hBMSCs). The patients undergoing hip arthroplasty were selected by inclusion/exclusion criteria for this study. The extracted hBMSCs were detected of osteogenic differentiation by alizarin red S staining, and of cell phenotype by flow cytometry. Bioinformatics, dual luciferase report, western blotting, RT‐PCR and immunoblotting were used in our study. The hBMSCs were divided into miR‐98 mimics, miR‐98 negative control (NC), miR‐98 inhibitors, Mock and miR‐98 inhibitors + siBMP2 groups. Human bone mesenchymal stromal cells were extracted and purified in vitro and had specific cytological morphology, surface markers and abilities of self‐renewal and differentiation. Compared with the NC group and Mock group, the miR‐98 mimics group showed increased miR‐98 level while the miR‐98 inhibitors group decreased miR‐98 level (both P < 0.01). Dual luciferase reporter showed BMP2 was the target gene of miR‐98. The levels of mRNA and protein expression of BMP2, protein expression of RUNX2, alkaline phosphatase activity and osteocalcin content significantly decreased in the miR‐98 mimics group while increased in the miR‐98 inhibitors group and showed no changes in the NC group and Mock group (all P < 0.05). The miR‐98 mimics group showed obviously declined stained red particles and the miR‐98 inhibitors group showed opposite result. After lowering the expression of miR‐98, osteogenic differentiation ability of hBMSCs rose, which was weakened by the transfection with siBMP2. miR‐98 may regulate osteogenic differentiation of hBMSCs by targeting BMP2.

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“…Increased expression of osterix (18) and Runx2 has been shown to be responsible for p38 in promoting osteogenesis. (19) The significance of MAPK signaling in bone development is substantiated by a study using a transgenic approach that demonstrates increased Runx2 phosphorylation and transcriptional activity in MEK1 transgenic mice (20) but not in mice expressing a dominant-negative MEK1 mutant. Little is known about the mechanisms regulating MAPK activation during osteoblast differentiation.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation

Lin

Chou

Hsieh

et al. 2010

Journal of Bone and Mineral Research

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Deficiency of the collagen receptor discoidin domain receptor tyrosine kinase (DDR2) in mice and humans results in dwarfism and short limbs, of which the mechanism remains unknown. Here we report that DDR2 is a key regulator of osteoblast differentiation. DDR2 mRNA expression was increased at an early stage of induced osteoblast differentiation. In the subchondral bone of human osteoarthritic knee, DDR2 was detected in osteoblastic cells. In mouse embryos, DDR2 expression was found from E11 to E15, preceding osteocalcin (OCN) and coinciding with Runx2 expression. Activating transcription factor 4 (ATF4) enhanced DDR2 mRNA expression, and knockdown of ATF4 expression delayed DDR2 induction during osteoblast differentiation. A CCAAT/enhancer binding protein (C/EBP) binding site at À1150 bp in the DDR2 promoter was required for ATF4-mediated DDR2 activation. C/EBPb bound to and cooperated with ATF4 in stimulating DDR2 transcription; accordingly, the ATF4 mutants deficient of C/EBPb binding were incapable of transactivating DDR2. Overexpression of DDR2 increased osteoblast-specific gene expression. Conversely, knockdown of DDR2 suppressed osteogenic marker gene expression and matrix mineralization during the induced osteogenesis. The stimulation of p38 MAPK by DDR2 was required for DDR2-induced activation of Runx2 and OCN promoters. Together our findings uncover a pathway in which ATF4, by binding to C/EBPb transcriptionally upregulates DDR2 expression, and DDR2, in turn, activates Runx2 through p38 MAPK to promote osteoblast differentiation. ß

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Critical role of the extracellular signal–regulated kinase–MAPK pathway in osteoblast differentiation and skeletal development

Cited by 451 publications

References 53 publications

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

c-Jun N-terminal kinase 1 negatively regulates osteoblastic differentiation induced by BMP2 via phosphorylation of Runx2 at Ser104

MicroRNA‐98 regulates osteogenic differentiation of human bone mesenchymal stromal cells by targeting BMP2

Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation

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