Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells

Gallea, Sylvie; Lallemand, François; Atfi, Azeddine; Rawadi, Georges; Ramez, Valérie; Spinella-Jaegle, Sylviane; Kawai, Shinji; Faucheu, Chi; Huet, L; Baron, Roland; Roman-Roman, Sergio

doi:10.1016/s8756-3282(01)00415-x

Cited by 277 publications

(252 citation statements)

References 40 publications

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“…2). BMP have been shown to induce activation of p38 and ERK in other systems [22]. In Jurkat TAg cells we observed an increase in the levels of phospho-p38 and phospho-ERK1/2 after 1 h of stimulation, and this increase was sustained for at least 24 h (Fig.…”

Section: Bmp-6 Signalling and Target Genes In Jurkat Tag Cellssupporting

confidence: 52%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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Section: Bmp-6 Signalling and Target Genes In Jurkat Tag Cellssupporting

confidence: 52%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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“…In addition, BMP2 promotes osteoblastic differentiation in several cell types, such as multipotent myoblastic C2C12 cells, preosteoblastic MC3T3-E1 cells, primary calvarial osteoblasts, and bone marrow stromal cells. (9,21,30) BMP2 has been reported to activate ERK and p38 MAP kinases in the multipotent C2C12 cells, (11,38) and mainly activates JNK and p38 MAP kinases in MC3T3-E1 cells. (13) A previous study mentioned that JNK2 is mainly activated in the presence of osteogenic supplements (ascorbic acid, b-glycerophosphate, and dexamethasone).…”

Section: Discussionmentioning

confidence: 99%

“…(6,10) In addition to Smad signaling, mitogen-activated protein kinase (MAPK) cascade represents an alternative pathway for BMP2 signal transduction. (11)(12)(13)(14) MAPKs contain cjun-N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38, and their activation by BMP2 depends on cell types and experimental conditions. (15) Runx2 can be phosphorylated by BMP2-induced activation of MAPK pathways.…”

Section: Introductionmentioning

confidence: 99%

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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“…Although ERK and p38 MAPKs both have been reported as regulating osteoblast differentiation, (30,31) we have shown that the BMP-2-induced osteogenesis of C3H10T1/2 and C2C12 cells, which specifically enhanced DDR2 expression among all collagen receptors, is associated with increased phosphorylation of p38 but not ERK. Furthermore, while inhibition of ERK activity does not affect DDR2-dependent OCN promoter activation, inhibition of either the expression or activation of p38 abolishes Fig.…”

Section: Discussionmentioning

confidence: 61%

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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Activation of mitogen-activated protein kinase cascades is involved in regulation of bone morphogenetic protein-2-induced osteoblast differentiation in pluripotent C2C12 cells

Cited by 277 publications

References 40 publications

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

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

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

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