Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bone morphogenetic protein (BMP) and Wnt signaling pathways both contribute essential roles in regulating bone mass. However, the molecular interactions between these pathways in osteoblasts are poorly understood. We recently reported that osteoblast-targeted conditional knockout (cKO) of BMP receptor type IA (BMPRIA) resulted in increased bone mass during embryonic development, where diminished expression of Sost as a downstream effector of BMPRIA resulted in increased Wnt/beta-catenin signaling. Here, we report that Bmpr1a cKO mice exhibit increased bone mass during weanling stages, again with evidence of enhanced Wnt/beta-catenin signaling as assessed by Wnt reporter TOPGAL mice and TOPFLASH luciferase. Consistent with negative regulation of the Wnt pathway by BMPRIA signaling, treatment of osteoblasts with dorsomorphin, an inhibitor of Smad-dependent BMP signaling, enhanced Wnt signaling. In addition to Sost, Wnt inhibitor Dkk1 also was downregulated in cKO bone. Expression levels of Dkk1and Sost were upregulated by BMP2 treatment and downregulated by Noggin. Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype. These effectors are differentially regulated by mitogen-activated protein kinase (MAPK) p38 because pretreatment of osteoblasts with SB202190 blocked BMP2-induced Dkk1 expression but not Sost. These results demonstrate that BMPRIA in osteoblasts negatively regulates endogenous bone mass and Wnt/beta-catenin signaling and that this regulation may be mediated by the activities of Sost and Dkk1. This study highlights several interactions between BMP and Wnt signaling cascades in osteoblasts that may be amenable to therapeutic intervention for the modification of bone mass density.
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PMID:Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. 1987 86

We recently demonstrated that prolactin (PRL) prevents chronic stress-induced inhibition of adult hippocampal neurogenesis. It remained unsettled, however, whether PRL is acting directly on neural stem and progenitors cells (NPCs) or if neurogenesis is affected by an indirect mechanism, for example through the extensively described effects of PRL on the HPA axis. To address this point, we used neurosphere cultures derived from the adult rat hippocampus as an in vitro model for NPCs. Dexamethasone (DEX) was applied to stress the NPCs, and proliferation, survival and differentiation of cells were examined. DEX markedly inhibited proliferation of NPCs and cells entered the G(0) phase of cell cycle. Moreover, DEX reduced NPC survival and repressed astroglial differentiation, which is normally induced by serum or bone morphogenetic protein application. Even though we could demonstrate that NPCs express the PRL receptor and ERK1/2 signaling is induced by PRL, we did not observe any effect of PRL on NPCs proliferation, differentiation or survival, neither in the presence nor during absence of DEX. In summary, our results indicate that PRL action on NPCs and neurogenesis in vivo occurs via an indirect mechanism.
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PMID:Prolactin induces MAPK signaling in neural progenitors without alleviating glucocorticoid-induced inhibition of in vitro neurogenesis. 1991 Jun 80

Development of bone morphogenetic protein (BMP) signaling modulators may provide useful therapeutic options for the treatment of large bony defects in clinical settings. Controversy remains over whether hepatocyte growth factor (HGF) is a positive or negative modulator of BMP-induced osteogenesis. This study analyzed osteogenic properties of HGF, particularly during BMP-2-induced bone formation. Using a mouse model of ectopic bone formation, HGF-impregnated gelatin sponges displayed significantly reduced bone formation induced by BMP-2, both radiologically and histologically. Abrogation of endogenous HGF production by knockdown of HGF mRNA resulted in upregulation of BMP-2-induced ALP activity for C2C12 myoblasts in vitro. In contrast, addition of exogenous HGF inhibited BMP-2-induced ALP activity and osteocalcin production by mouse embryonic fibroblasts (MEFs) through HGF-c-Met interactions. Inhibition of ALP activity by HGF was rescued by U0126, a MEK1/2 inhibitor, indicating that HGF suppresses the BMP-2-Smad axis via activation of ERK1/2. Importantly, treatment with HGF prior to administration of BMP-2 induced cellular proliferation of MEFs and did not influence subsequent osteoblast differentiation induced by BMP-2. The effects of HGF may differ according to the differentiation stage of mesenchymal stem cells, which would explain the inconsistencies seen in osteogenic properties of HGF in previous reports. The timing of HGF treatment is critical and should be carefully determined for successful induction of bone formation by BMPs.
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PMID:The effect of timing in the administration of hepatocyte growth factor to modulate BMP-2-induced osteoblast differentiation. 1991 94

Here, we show the involvement of signaling pathways to induce the gene expression of bone morphogenetic protein (BMP) in the osteogenic activity of physcion-8-O-beta-D-glucopyranoside (physcion-Glu); it stimulated osteoblast differentiation in mouse osteoblast MC3T3-E1 subclone 4 cells and induced BMP-2 gene expression and activation of Akt and ERK/MAP kinases. Physcion-Glu-induced BMP-2 expression and mineralization were attenuated by LY294002, an inhibitor of PI3K that lies upstream of Akt and MAP kinases, suggesting that physcion-Glu induces osteoblast differentiation via PI3K-Akt/MAP kinase signaling pathways, which play important roles in inducing BMP-2 gene expression. Physcion-Glu also enhanced BMP-2-induced commitment of mouse bi-potential mesenchymal precursor C2C12 cells into osteoblasts while inducing the transcription of several osteogenic BMP isoforms, such as BMP-2, -4, -7, and -9. Osteogenic synergy between BMP-2 and physcion-Glu was supported by the fact that noggin inhibited BMP-2 and physcion-Glu-induced alkaline phosphatase expression and activity. Considering that physcion-Glu induced Runx2 activity and the nuclear translocation of p-Smad, physcion-Glu could act by enhancing the BMP signaling pathway that induces Smad activation and translocation to activate Runx2. In conclusion, physcion-Glu could enhance the commitment of mesenchymal progenitors into osteoblasts and their differentiation by activating signaling pathways to induce BMP gene expression.
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PMID:Physcion-8-O-beta-D-glucopyranoside enhances the commitment of mouse mesenchymal progenitors into osteoblasts and their differentiation: Possible involvement of signaling pathways to activate BMP gene expression. 2010 54

Periprosthetic osteolysis of joint replacements caused by wear debris is a significant complication of joint replacements. Polymethylmethacrylate (PMMA) particles have been shown to inhibit osteogenic differentiation, but the molecular mechanism has not been previously determined. In this study, we exposed differentiating MC3T3-E1 preostoblast cells to PMMA particles and determined the changes that occurred with respect to p38 mitogen-activated protein kinase (MAPK) activity and the transforming growth factor (TGF)-beta1 and bone morphogenetic protein (BMP) signaling pathways. In the absence of particles, MC3T3-E1 cells demonstrate activation of p38 MAPK on day 8 of differentiation; however, when treated with PMMA particles, differentiating MC3T3-E1 cells demonstrate the suppression of p38 activity on day 8 and show activation of p38 on days 1 and 4. On day 4 of particle exposure, the differentiating MC3T3-E1 cells show significant downregulation of TGF-beta1 expression, which is involved in osteoblast differentiation, and a significant upregulation of the expression of BMP3 and Sclerostin (SOST), which are negative regulators of osteoblast differentiation. By day 8 of particle exposure, the changes in TGF-beta1, BMP3, and SOST expression are opposite of those seen on day 4. This study has demonstrated the distinct changes in the molecular profile of MC3T3-E1 cells during particle-induced inhibition of osteoblast differentiation. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.
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PMID:Polymethylmethacrylate particle exposure causes changes in p38 MAPK and TGF-beta signaling in differentiating MC3T3-E1 cells. 2016 19

Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1- and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1- and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11betaHSD2 (11beta-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH.
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PMID:Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension. 2018 46

The importance of canonical transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling during cartilage and joint development is well established, but the necessity for noncanonical (SMAD-independent) signaling during these processes is largely unknown. TGF-beta activated kinase 1 (TAK1) is a MAP3K activated by TGF-beta, BMP, and other mitogen-activated protein kinase (MAPK) signaling components. We set out to define the potential role for noncanonical, TAK1-mediated signaling in cartilage and joint development via deletion of Tak1 in chondrocytes (Col2Cre;Tak1(f/f)) and the developing limb mesenchyme (Prx1Cre;Tak1(f/f)). Deletion of Tak1 in chondrocytes resulted in novel embryonic developmental cartilage defects including decreased chondrocyte proliferation, reduced proliferating chondrocyte survival, delayed onset of hypertrophy, reduced Mmp13 expression, and a failure to maintain interzone cells of the elbow joint, which were not observed previously in another Col2Cre;Tak1(f/f) model. Deletion of Tak1 in limb mesenchyme resulted in widespread joint fusions likely owing to the differentiation of interzone cells to the chondrocyte lineage. The Prx1Cre;Tak1(f/f) model also allowed us to identify novel columnar chondrocyte organization and terminal maturation defects owing to the interplay between chondrocytes and the surrounding mesenchyme. Furthermore, both our in vivo models and in vitro cell culture studies demonstrate that loss of Tak1 results in impaired activation of the downstream MAPK target p38, as well as diminished activation of the BMP/SMAD signaling pathway. Taken together, these data demonstrate that TAK1 is a critical regulator of both MAPK and BMP signaling and is necessary for proper cartilage and joint development.
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PMID:TAK1 regulates cartilage and joint development via the MAPK and BMP signaling pathways. 2021 96

Dental pulp cells, which have been shown to share phenotypical features with osteoblasts, are capable of differentiating into odontoblast-like cells and generating a dentin-like mineral structure. Elevated extracellular Ca(2+)Ca(2+)(o) has been implicated in osteogenesis by stimulating the proliferation and differentiation of osteoblasts; however, the role of Ca(2+)(o) signaling in odontogenesis remains unclear. We found that elevated Ca(2+)(o) increases bone morphogenetic protein (BMP)-2 gene expression in human dental pulp cells. The increase was modulated not only at a transcriptional level but also at a post-transcriptional level, because treatment with Ca(2+) increased the stability of BMP-2 mRNA in the presence of actinomycin D, an inhibitor of transcription. A similar increase in BMP-2 mRNA level was observed in other human mesenchymal cells from oral tissue; periodontal ligament cells and gingival fibroblasts. However, the latter cells exhibited considerably lower expression of BMP-2 mRNA compared with dental pulp cells and periodontal ligament cells. The BMP-2 increase was markedly inhibited by pretreatment with an extracellular signal-regulated kinase (ERK) inhibitor, PD98059, and partially inhibited by the L-type Ca(2+) channels inhibitor, nifedipine. However, pretreatment with nifedipine had no effect on ERK1/2 phosphorylation triggered by Ca(2+), suggesting that the Ca(2+) influx from Ca(2+) channels may operate independently of ERK signaling. Dental pulp cells do not express the transcript of Ca(2+)-sensing receptors (CaSR) and only respond slightly to other cations such as Sr(2+) and spermine, suggesting that dental pulp cells respond to Ca(2+)(o) to increase BMP-2 mRNA expression in a manner different from CaSR and rather specific for Ca(2+)(o) among cations.
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PMID:Elevated extracellular calcium increases expression of bone morphogenetic protein-2 gene via a calcium channel and ERK pathway in human dental pulp cells. 2034 18

Human neurodegenerative diseases are devastating illnesses that predominantly affect elderly people. The majority of the diseases are associated with pathogenic oligomers from misfolded proteins, eventually causing the formation of aggregates and the progressive loss of neurons in the brain and nervous system. Several of these proteinopathies are sporadic and the cause of pathogenesis remains elusive. Heritable forms are associated with genetic defects, suggesting that the affected protein is causally related to disease formation and/or progression. The limitations of human genetics, however, make it necessary to use model systems to analyse affected genes and pathways in more detail. During the last two decades, research using the genetically amenable fruitfly has established Drosophila melanogaster as a valuable model system in the study of human neurodegeneration. These studies offer reliable models for Alzheimer's, Parkinson's, and motor neuron diseases, as well as models for trinucleotide repeat expansion diseases, including ataxias and Huntington's disease. As a result of these studies, several signalling pathways including phosphatidylinositol 3-kinase (PI3K)/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) and bone morphogenetic protein (BMP) signalling, have been shown to be deregulated in models of proteinopathies, suggesting that two or more initiating events may trigger disease formation in an age-related manner. Moreover, these studies also demonstrate that the fruitfly can be used to screen chemical compounds for their potential to prevent or ameliorate the disease, which in turn can directly guide clinical research and the development of novel therapeutic strategies for the treatment of human neurodegenerative diseases.
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PMID:Drosophila melanogaster in the study of human neurodegeneration. 2052 7

Reduced bone morphogenetic protein (BMP) receptor (BMPR) expression and BMP signaling have been implicated in vascular cell proliferation and remodeling associated with pulmonary arterial hypertension (PAH). The low penetrance of the BMPR II disease gene in familial PAH suggests that additional genetic or environmental factors are involved in clinical manifestation of PAH. Smurf1 ubiquitin ligase, together with inhibitory SMAD 6/7, forms a negative feedback loop for the attenuation of BMP signals by downregulating BMPR and signaling molecules and, in addition, functions in the integration of MAPK/Ras mitogenic pathways. The present study found that Smurf1 was significantly elevated in pulmonary arteries of monocrotaline and hypoxia-induced PAH rats. In the pulmonary artery of hypoxia-exposed mice, elevation of Smurf1 and SMAD7 was correlated with reduced expression of BMPR II protein. Over-expression of Smurf1 in cultured cells induced ubiquitination and degradation of BMPR I and II whereas ligase-inactive Smurf1 reduced ubiquitination and elevated their protein levels, thus serving a dominant-negative function. Smurf1-induced receptor degradation was inhibited by both proteasomal and lysosomal inhibitors. Thus, Smurf1 reduces steady-state levels of BMPRs by ubiquitination and subsequent degradation involving proteasomes and lysosomes. Therefore, these results show that Smurf1 induction could be a key event for triggering downregulation of BMP signaling and causing vascular cell proliferation and remodeling in PAH and that abrogating Smurf1 function could be a strategy for PAH therapeutics.
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PMID:Smurf1 ubiquitin ligase causes downregulation of BMP receptors and is induced in monocrotaline and hypoxia models of pulmonary arterial hypertension. 2055 34


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