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)

Cx3cl1, also called fractalkine, is located at 19p12, and encodes the chemokine (C-X3-C motif) ligand 1 protein. This protein contains 393 amino acids, and is the only member of the chemokine CX3C subfamily. CX3CR1 is the specific receptor of Cx3cl1, and the binding of this ligand and its receptor participates in a variety of physiological and pathological processes. Through employing microarray technology we demonstrated for the first time that Cx3cl1 was upregulated in osteogenic-induced rat bone marrow mesenchymal stem cells (BMSCs). To analyze the gene expression profiling of Cx3cl1 in osteogenic-induced rat BMSCs at different times, real-time quantitative polymerase chain reaction (real-time PCR) was used to assay Cx3cl1 mRNA. The results showed that the expression of Cx3cl1 in osteogenic-induced rat BMSCs increased consistently for 28 days with a peak at day 21, and Cx3cl1 may be correlated with osteogenic differentiation of BMSCs. Based on bioinformatic analyses, we hypothesize that Cx3cl1 may be beneficial to the formation of the osteoplastic microenvironment by regulating cellular distribution and aggregation, and by promoting cellular mutual induction and paracrine. Cx3cl1 may also be involved in osteogenic differentiation and bone formation of BMSCs through an increase in Runx2 transcription by activating p38 mitogen-activated protein kinase (MAPK).
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PMID:Gene expression profiling of Cx3cl1 in bone marrow mesenchymal stem cells by osteogenic induction. 1942 92

Previous studies have indicated that periodontal ligament (PDL) cells demonstrate osteogenic potential and osteoblastic differentiation via the extracellular signal-regulated kinase (ERK) pathway under mechanical stress in vitro and in vivo. This study aimed to further analyse this regulatory process experimentally in the rat. The right upper first molars of 25 twelve-week-old male Wistar anaesthetized rats were loaded with forces in order to be moved mesially. Constant forces for 4 hours of 0.25 and 0.5 N were applied in five animals each. Furthermore, constant forces for 2 hours of 0.1 N were applied in 10 animals and afterwards, the first and second molars were permanently separated with composite. In these animals, the antagonists were sliced and five rats were killed after 1 day and five after 2 days. As a last experiment, intermittent forces of 0.1 N and 0.25 Hz were applied in five different animals for 4 hours. The untreated contralateral sides served as the control. Paraffin-embedded sections were analysed by immunohistochemistry for proliferating cell nuclear antigen (PCNA), runt-related transcription factor 2 (Runx2/Cbfa1), and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). Statistical analysis to determine differences between the groups was carried out using a Student's t-test. In selected areas under tension, the proportion of pERK1/2-positive cells was increased compared with those in control teeth under all types of loading, whereas these proportions in selected areas under pressure were increased only after the application of intermittent forces. In representative areas, both under tension and pressure, the proportion of Runx2-positive cells decreased after the application of constant forces. After the application of constant forces for 4 hours in representative areas, both under tension and pressure, the proportion of PCNA-positive cells was lower than those in control teeth. The involvement of pERK1/2, Runx2/cbfa-1, and PCNA in the reaction of PDL cells to different load regimens was verified.
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PMID:Proliferation and differentiation of periodontal ligament cells following short-term tooth movement in the rat using different regimens of loading. 1963 44

Adult human mesenchymal stem cells (MSCs) hold promise for an increasing list of therapeutic uses due to their ease of isolation, expansion, and multi-lineage differentiation potential. To maximize the clinical potential of MSCs, the underlying mechanisms by which MSC functionality is controlled must be understood. We have taken a deconstructive approach to understand the individual components in vitro, namely the role of candidate "stemness" genes. Our recent microarray gene expression profiling data suggest that interleukin-6 (IL-6) may contribute to the maintenance of MSCs in their undifferentiated state. In this study, we showed that IL-6 gene expression is significantly higher in undifferentiated MSCs as compared to their chondrogenic, osteogenic, and adipogenic derivatives. Moreover, we found that MSCs secrete copious amounts of IL-6 protein, which decreases dramatically during osteogenic differentiation. We further evaluated the role of IL-6 for maintenance of MSC "stemness," using a series of functional assays. The data showed that IL-6 is both necessary and sufficient for enhanced MSC proliferation, protects MSCs from apoptosis, inhibits adipogenic and chondrogenic differentiation of MSCs, and increases the rate of in vitro wound healing of MSCs. We further identified ERK1/2 activation as the key pathway through which IL-6 regulates both MSC proliferation and inhibition of differentiation. Taken together, these findings show for the first time that IL-6 maintains the proliferative and undifferentiated state of bone marrow-derived MSCs, an important parameter for the optimization of both in vitro and in vivo manipulation of MSCs.
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PMID:Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. 1965 Jan 10

FGF2 has been shown to enhance proliferation and maintain differentiation potential in hMSCs during in vitro propagation. In this study, we investigated the role of mitogen-activated protein kinase in the functions of FGF2 in hMSCs. We demonstrated that FGF2 induces the transient activation of c-Jun N-terminal kinase (JNK), but not extracellular signal-regulated protein kinase or p38 protein kinase. SP600125 and a dominant negative JNK1 significantly reduced the FGF2-enhanced proliferation of hMSCs. Treatment with SP600125 also diminished the activity of FGF2 in the maintenance of adipogenic and osteogenic differentiation potential. These results suggest that JNK signaling is involved in the FGF2-induced stimulation of the proliferation and the maintenance of differentiation potential in hMSCs.
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PMID:FGF2 stimulates the proliferation of human mesenchymal stem cells through the transient activation of JNK signaling. 1966 26

Adult human mesenchymal stromal cells (hMSCs) have the potential to differentiate into chondrogenic, adipogenic, or osteogenic lineages, providing a potential source for tissue regeneration. An important issue for efficient bone regeneration is to identify factors that can be targeted to promote the osteogenic potential of hMSCs. Using transcriptome analysis, we found that integrin alpha5 (ITGA5) expression is up-regulated during dexamethasone-induced osteoblast differentiation of hMSCs. Gain-of-function studies showed that ITGA5 promotes the expression of osteoblast phenotypic markers and in vitro osteogenesis of hMSCs. Down-regulation of endogenous ITGA5 using specific shRNAs blunted osteoblast marker gene expression and osteogenic differentiation. Molecular analyses showed that the enhanced osteoblast differentiation induced by ITGA5 was mediated by activation of focal adhesion kinase/ERK1/2-MAPKs and PI3K signaling pathways. Remarkably, activation of endogenous ITGA5 using agonists such as a specific antibody that primes the integrin or a peptide that specifically activates ITGA5 was sufficient to enhance ERK1/2-MAPKs and PI3K signaling and to promote osteoblast differentiation and osteogenic capacity of hMSCs. Importantly, we demonstrated that hMSCs engineered to overexpress ITGA5 exhibited a marked increase in their osteogenic potential in vivo. Taken together, these findings not only reveal that ITGA5 is required for osteoblast differentiation of adult hMSCs but also provide a targeted strategy using ITGA5 agonists to promote the osteogenic capacity of hMSCs. This may be used for tissue regeneration in bone disorders where the recruitment or capacity of hMSCs is compromised.
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PMID:Priming integrin alpha5 promotes human mesenchymal stromal cell osteoblast differentiation and osteogenesis. 1984 92

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

Patients with diabetes tend to have an increased incidence of osteoporosis that may be related to hyperglycemia. In this study, we investigated the effects of high glucose on differentiation of human osteoblastic MG-63 cells and involved intracellular signal transduction pathways. Here, we showed that high glucose suppressed the cell growth, mineralization, and expression of osteogenic markers including Runx2, collagen I, osteocalcin, osteonectin, but inversely promoted expression of adipogenic markers including PPARgamma, aP2, resistin, and adipsin. Moreover, high glucose significantly increased the intracellular cAMP level in a time-dependent manner and induced ERK1/2 activation. Meanwhile, supplementation of H89, a specific inhibitor of PKA, and PD98059, a specific inhibitor of MAPK/ERK kinase, reversed the cell growth inhibition, the down-regulation of osteogenic markers and the up-regulation of adipogenic markers as well as the activation of ERK under high glucose. These results indicate that high glucose can increase adipogenic and inhibit osteogenic differentiation by activating cAMP/PKA/ERK pathway in MG-63 cells, thereby providing further insight into the molecular mechanism of diabetic osteoporosis.
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PMID:High glucose stimulates adipogenic and inhibits osteogenic differentiation in MG-63 cells through cAMP/protein kinase A/extracellular signal-regulated kinase pathway. 1994 37

Extracellular matrix (ECM) plays a fundamental role in angiogenesis affecting endothelial cells proliferation, migration and differentiation. Vessels-like network formation in vitro is a reliable test to study the inductive effects of ECM on angiogenesis. Here we utilized matrix deposed by osteoblasts as substrate where the molecular and structural complexity of the endogenous ECM is preserved, to test if it induces vessel-like network formation by endothelial cells in vitro. ECM is more similar to the physiological substrate in vivo than other substrates previously utilized for these studies in vitro. Osteogenic ECM, prepared in vitro from mature osteoblasts at the phase of maximal deposition and glycosylation of collagen I, induces EAhy926, HUVEC, and HDMEC endothelial cells to form vessels-like structures and promotes the activation of metalloproteinase-2 (MMP-2); the functionality of the p-38/MAPK signaling pathway is required. Osteogenic ECM also induces a transient increase of CXCL12 and a decrease of the receptor CXCR4. The induction of vessel-like networks is dependent from proper glycosylation of collagens and does not occur on osteogenic ECMs if deglycosylated by -galactosidase or on less glycosylated ECMs derived from preosteoblasts and normal fibroblasts, while is sustained on ECM from osteogenesis imperfecta fibroblasts only when their mutation is associated with over-glycosylation of collagen type I. These data support that post-translational glycosylation has a role in the induction in endothelial cells in vitro of molecules conductive to self-organization in vessels-like structures.
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PMID:Osteoblasts extracellular matrix induces vessel like structures through glycosylated collagen I. 2000 3

Increasing adipocyte size as well as numbers is important in the development of obesity and type 2 diabetes, with adipocytes being generated from mesenchymal precursor cells. This process includes the determination of mesenchymal stem cells (MSC) into preadipocytes (PA) and the differentiation of PA into mature fat cells. Although the process of differentiation has been highly investigated, the determination in humans is poorly understood. In this study, we compared human MSC and human committed PA on a cellular and molecular level to gain further insights into the regulatory mechanisms in the determination process. Both cell types showed similar morphology and expression patterns of common mesenchymal and hematopoietic surface markers. However, although MSC were able to differentiate into adipocytes and osteocytes, PA were only able to undergo adipogenesis, indicating that PA lost their multipotency during determination. WNT-5a expression showed significantly higher levels in MSC compared with PA suggesting that WNT-5a down-regulation might be important in the determination process. Indeed, incubation of human MSC in medium containing neutralizing WNT-5a antibodies abolished their ability to undergo osteogenesis, although adipogenesis was still possible. An opposite effect was achieved using recombinant WNT-5a protein. On a molecular level, WNT-5a was found to promote c-Jun N-terminal kinase-dependent intracellular signaling in MSC. Activation of this noncanonical pathway resulted in the induction of osteopontin expression further indicating pro-osteogenic effects of WNT-5a. Our data suggest that WNT-5a is necessary to maintain osteogenic potential of MSC and that inhibition of WNT-5a signaling therefore plays a role in their determination into PA in humans.
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PMID:Role of WNT-5a in the determination of human mesenchymal stem cells into preadipocytes. 2003 69

Hypoxia has been considered to affect the properties of tissue stem cells including mesenchymal stem cells (MSCs). Effects of long periods of exposure to hypoxia on human MSCs, however, have not been clearly demonstrated. MSCs cultured under normoxic conditions (20% pO(2)) ceased to proliferate after 15-25 population doublings, while MSCs cultured under hypoxic conditions (1% pO(2)) retained the ability to proliferate with an additional 8-20 population doublings. Most of the MSCs cultured under normoxic conditions were in a senescent state after 100days, while few senescent cells were found in the hypoxic culture, which was associated with a down-regulation of p16 gene expression. MSCs cultured for 100days under hypoxic conditions were superior to those cultured under normoxic conditions in the ability to differentiate into the chondro- and adipogenic, but not osteogenic, lineage. Among the molecules related to mitogen-activated protein kinase (MAPK) signaling pathways, extracellular signal regulated kinase (ERK) was significantly down-regulated by hypoxia, which helped to inhibit the up-regulation of p16 gene expression. Therefore, the hypoxic culture retained MSCs in an undifferentiated and senescence-free state through the down-regulation of p16 and ERK.
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PMID:Mesenchymal stem cells cultured under hypoxia escape from senescence via down-regulation of p16 and extracellular signal regulated kinase. 2003 68


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