Signal Transductions Induced by Bone Morphogenetic Protein-2 and Transforming Growth Factor-β in Normal Human Osteoblastic Cells

Lai, Chung-Fang; Cheng, Su‐Li

doi:10.1074/jbc.m200794200

Cited by 212 publications

(178 citation statements)

References 70 publications

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“…BTC, EGF, and TGFA)-mediated inhibitory signaling via MAP kinase/ERK . It is well established that BMP2 receptor signaling occurs via SMAD1/5/8, and there are various reports that BMP2 can also activate MAP kinase/ERK signaling in a latent and prolonged fashion (Lou et al 2000, Lai & Cheng 2002). Although we found no evidence for this in the present study, it is premature to dismiss the possibility for BMPinduced MAP kinase/ERK signaling in the hen granulosa cells.…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 2 inhibits FSH responsiveness in hen granulosa cells

Haugen¹,

Johnson²

2010

Reproduction

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Prior to follicle selection into the preovulatory hierarchy, hen granulosa cells from prehierarchal follicles remain undifferentiated, as defined in part by the virtual absence of LHR mRNA expression and inability to produce progesterone. It has previously been proposed that prior to follicle selection, granulosa cells are actively maintained in an undifferentiated state by epidermal growth factor receptor ligands (EGFRL) signaling via the MAP kinase/extracellular regulated kinase pathway. Moreover, there is recent evidence that EGFRL/MAP kinase signaling modulates FSH receptor (FSHR) transcription, in part, via inhibitor of differentiation/DNA-binding (ID) proteins. In the present studies with undifferentiated granulosa, recombinant human (rh) bone morphogenetic protein 2 (BMP2) induced the phosphorylation of SMAD1/5/8, and blocked transforming growth factor b and FSH-induced FSHR expression and progesterone production. Significantly, BMP2 rapidly induced mRNAs encoding betacellulin and EGF, plus ID proteins (ID1, ID3, and ID4). Alternatively, the bioactivity of BMPs can be modulated by one or more BMP antagonists, including noggin (NOG). NOG mRNA is expressed by both hen granulosa and theca tissues from prehierarchal follicles. Pretreatment of cultured granulosa with rh NOG reversed both the stimulatory effects of BMP2 on ID1, ID3, and ID4 expression and the inhibitory effects of BMP2 on FSHR mRNA levels and progesterone production. Collectively, these data provide evidence that prior to follicle selection, BMP2 signaling contributes toward maintaining granulosa cells in an undifferentiated state. The actions of BMP2 are, at least in part, mediated indirectly via enhanced EGFRL expression and ERBB receptor-mediated MAP kinase signaling, and can be modulated by the autocrine/paracrine production of NOG.

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 2 inhibits FSH responsiveness in hen granulosa cells

Haugen¹,

Johnson²

2010

Reproduction

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“…It has been demonstrated in osteoblasts that BMP2 can stimulate RAS/MAPK activity [21]. We assessed if BMP2 treatment can stimulate phospho-ERK activity in FET cells.…”

Section: Bmp-smad Signaling and Growth Suppression Is Modulated By K-mentioning

confidence: 99%

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

Beck

Jung

Rosario

et al. 2007

Cellular Signalling

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Bone morphogenetic proteins (BMPs) regulate cell differentiation, proliferation, and apoptosis through a canonical SMAD signaling cascade. Absence of BMP signaling causes the formation of intestinal juvenile polyps in the colon cancer-prone syndrome familial juvenile polyposis. As sporadic colon cancers appear to have intact BMP signaling, we evaluated if K-RAS, driving a mitogenic pathway frequently activated in colon cancer, negatively affects BMP growth suppression. We treated non-tumorigenic but activated RAS/ERK FET cells with BMP2, and in combination with pharmacological or genetic inhibition of RAS/ERK, examined BMP-SMAD signaling, transcriptional activity, and cell growth, and also assessed p21 WAF1 mRNA, transcriptional activation, and protein levels. BMP2 increased nuclear phospho-SMAD1 2-fold, which increased another 2-3 fold when RAS/ERK was inhibited. BMP2 increased BMP-specific SMAD transcriptional activity 2-fold over control and decreased cell growth, but inhibition of RAS/ERK further enhanced BMP-specific transcriptional activity by an additional 1.5-2 fold and enhanced growth suppression by 20%. BMP-induced growth suppression is mediated in part by p21 WAF1 , not by transcriptional upregulation but by improved p21 protein stability, which is inhibited by RAS/ERK. In colon cancer cells, BMP-SMAD signaling and growth suppression is facilitated by p21 WAF1 but modulated by oncogenic K-RAS to reduce the growth suppression directed by this pathway.

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“…(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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Signal Transductions Induced by Bone Morphogenetic Protein-2 and Transforming Growth Factor-β in Normal Human Osteoblastic Cells

Cited by 212 publications

References 70 publications

Bone morphogenetic protein 2 inhibits FSH responsiveness in hen granulosa cells

Bone morphogenetic protein 2 inhibits FSH responsiveness in hen granulosa cells

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

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

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