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)

Converging lines of evidence suggest that lanthanum tends to deposit in bone. The influence of lanthanum ion (La3+) on osteoblast differentiation and the related mechanism are essential to understanding its effect on bone metabolism. In this study, La3+ treatment enhanced in vitro osteoblast differentiation as evidenced by promoting alkaline phosphatase (ALP) activity, osteocalcin (OC) secretion, and matrix mineralization. The expressions of osteoblast-specific genes of Cbfa-1, osteopontin (OPN), and bone sialoprotein (BSP) were all increased in the presence of La3+, but no change was observed in that of type I collagen (COL-I). Further studies demonstrated that La3+ treatment enhanced phosphorylation of extracellular signal-regulated kinase (ERK). Inhibition of ERK activation by U0126 suppressed the effects of La3+ on osteoblast activity. Moreover, pretreatment of the cells with pertussis toxin (PTx), a Gi protein inhibitor, suppressed the La3+-enhanced ERK phosphorylation and osteoblast differentiation. These findings suggest that La3+ exposure enhances in vitro osteoblast differentiation and the effect depends on ERK phosphorylation via PTx-sensitive Gi protein signaling.
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PMID:Lanthanum enhances in vitro osteoblast differentiation via pertussis toxin-sensitive gi protein and ERK signaling pathway. 1909 34

Poly(vinyl alcohol) (PVA) has been widely used in the field of biomedical applications because of its hydrophilic properties for desired functions. Nonetheless, the role of PVA in tooth germ (TG) cell differentiation and mineralization has seldom been explored. To test the capacity of PVA in regulating TG cell differentiation and mineralization, TG cells obtained from 4-day-old Wistar rats were cultured on the PVA substrate. It was found that PVA was able to promote TG cell exhibiting high levels of alkaline phosphatase (ALP) activity, mineralization, and mRNA expression of osteocalcin (OCN), osteopontin (OPN), dentin matrix protein 1 (DMP1) and enamelin. Even when the additives routinely administrated in the differentiation medium such as dexamethasone, beta-glycerophosphate and ascorbic acid were removed from the culture system, PVA itself still stimulated TG cells with the differentiation and mineralization ability. By showing the direct suppression of extracellular signaling-regulated kinase1/2 (ERK1/2) of TG cells treated with U0126, known to suppress the activation of ERK1/2, and significant synergistic effects between PVA and U0126, we demonstrated the suppression of ERK1/2 pathway is one of the effects of PVA-promoted TG cell differentiation and mineralization. Taken together, this study demonstrated a novel role of PVA in promoting the differentiation and mineralization of TG cells through ERK1/2 acting as a negative regulator.
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PMID:Induction of differentiation and mineralization in rat tooth germ cells on PVA through inhibition of ERK1/2. 1900 Jun 37

AMP-activated protein kinase (AMPK) and Rho kinase (ROK) are known to modulate the mevalonate pathway. Activation of AMPK suppresses 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase. ROK acts downstream of HMG-CoA reductase, and its inhibition exerts antiatherosclerosis effects. However, whether or not these enzymes are involved in bone metabolism is unclear. The present study was undertaken to investigate the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide1-beta-d-ribonucleoside (AICAR), and a ROK inhibitor, fasudil hydrochrolide, on the mineralization of osteoblastic MC3T3-E1 cells. Real-time PCR and mineralization stainings revealed that both AICAR and fasudil significantly stimulated endothelial nitric oxide synthase (eNOS), bone morphogenetic protein-2 (BMP-2), and osteocalcin mRNA expression as well as mineralization in the cells. Supplementation of either mevalonate or geranyl-geranyl pyrophosphate, the downstream molecules of HMG-CoA reductase, or coincubation with either a nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester, or a BMP-2 antagonist, noggin, significantly reversed these AICAR-induced reactions. Western blot analysis showed that AICAR activated protein kinase B and extracellular signal-regulated kinase (ERK). ERK inhibitor significantly reversed the AICAR-induced increase in eNOS and BMP-2 mRNA expression. Measurement of ROK activities by enzyme-linked immunosorbent assay revealed that both AICAR and fasudil significantly suppressed the phosphorylation of the myosin-binding subunit of myosin phosphate, a ROK substrate. These findings suggest that the AMPK activator and the ROK inhibitor are able to stimulate the mineralization of osteoblasts through modulating the mevalonate pathway. These agents could be candidate drugs that promote bone formation for the treatment of osteoporosis.
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PMID:Activation of AMP kinase and inhibition of Rho kinase induce the mineralization of osteoblastic MC3T3-E1 cells through endothelial NOS and BMP-2 expression. 1900 47

Osteoblasts differentiate from mesodermal progenitors and play a pivotal role in bone formation and mineralization. Several transcription factors including runt-related transcription factor 2 (RUNX2), Osterix (OSX), and activating transcription factor4 (ATF4) are known to be crucial for the process, whereas the upstream signal transduction controlling the osteoblast differentiation sequence is largely unknown. Here, we explored the role of c-jun N-terminal kinase (JNK) in osteoblast differentiation using in vitro differentiation models of primary osteoblasts and MC3T3-E1 cells with ascorbic acid/beta-glycerophosphate treatment. Terminal osteoblast differentiation, represented by matrix mineralization, was significantly inhibited by the inactivation of JNK with its specific inhibitor and exogenous overexpression of MKP-M (MAP kinase phosphatase isolated from macrophages), which preferentially inactivates JNK. Conversely, enhanced mineral deposition was observed by inducible overexpression of p54(JNK2), whereas it was not observed by the overexpression of p46(JNK1) or p46(JNK2), indicating a distinct enhancing role of p54(JNK2) in osteoblast differentiation. Inactivation of JNK significantly inhibited late-stage molecular events of osteoblast differentiation, including gene expression of osteocalcin (Ocn) and bone sialoprotein (Bsp). In contrast, earlier differentiation events including alkaline phosphatase (ALP) activation and osteopontin (Opn) expression were not inhibited by JNK inactivation. Although the expression levels of two transcription factor genes, Runx2 and Osx, were not significantly affected by JNK inactivation, induction of Atf4 mRNA during osteoblast differentiation was significantly inhibited. Taken together, these data indicate that JNK activity is specifically required for the late-stage differentiation events of osteoblasts.
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PMID:JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation. 1901 86

The compliance of the extracellular matrix (ECM) regulates osteogenic differentiation by modulating extracellular signal-regulated kinase (ERK) activity. However, the molecular mechanism linking ECM compliance to the ERK-mitogen-activated protein kinase (MAPK) pathway remains unclear. Furthermore, RhoA has been widely implicated in integrin-mediated signaling and mechanotransduction. We studied the relationship between RhoA and ERK-MAPK signaling to determine their roles in the regulation of osteogenesis by ECM compliance. Inhibition of RhoA and ROCK in MC3T3-E1 pre-osteoblasts cultured on substrates of varying compliance reduced ERK activity, whereas constitutively active RhoA enhanced it. The expression of RUNX2, a potent osteogenic transcription factor, was increased on stiffer matrices and correlated with elevated ERK activity. Inhibition of RhoA, ROCK, or the MAPK pathway diminished RUNX2 activity and delayed the onset of osteogenesis as shown by altered osteocalcin (OCN) and bone sialoprotein (BSP) gene expression, alkaline phosphatase (ALP) activity, and matrix mineralization. These data establish that one possible mechanism by which ECM rigidity regulates osteogenic differentiation involves MAPK activation downstream of the RhoA-ROCK signaling pathway.
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PMID:ECM compliance regulates osteogenesis by influencing MAPK signaling downstream of RhoA and ROCK. 1911 8

We previously showed that the mitogen-activated protein (MAP) kinase superfamily, p44/p42 MAP kinase, p38 MAP kinase, and stress-activated protein kinase (SAPK)/c-Jun N-terminal (JNK), positively plays a part in the platelet-derived growth factor-BB- (PDGF-BB-) stimulated synthesis of interleukin-6 (IL-6), a potent bone resorptive agent, in osteoblast-like MC3T3-E1 cells while Akt and p70 S6 kinase negatively regulates the synthesis. In the present study, we investigated whether (-)-epigallocatechin gallate (EGCG), one of the major green tea flavonoids, affects the synthesis of IL-6 in these cells and the mechanism. EGCG significantly reduced the IL-6 synthesis and IL-6 mRNA expression stimulated by PDGF-BB, EGCG reduced the PDGF-BB-stimulated IL-6 synthesis also in primary-cultured osteoblasts. EGCG had no effect on the levels of osteocalcin and osteoprotegerin in MC3T3-E1 cells. The PDGF-BB-induced autophosphorylation of PDGF receptor beta was not suppressed by EGCG. The PDGF-BB-induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase was not affected by EGCG. On the other hand, EGCG markedly suppressed the PDGF-BB-induced phosphorylation of SAPK/JNK. Finally, the PDGF-BB-induced phosphorylation of Akt and p70 S6 kinase was not affected by EGCG. These results strongly suggest that EGCG inhibits the PDGF-BB-stimulated synthesis of IL-6 via suppression of SAPK/JNK pathway in osteoblasts.
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PMID:(-)-Epigallocatechin gallate reduces platelet-derived growth factor-BB-stimulated interleukin-6 synthesis in osteoblasts: suppression of SAPK/JNK. 1914 96

Arterial calcification is common, but the mechanisms remain unclear. This study was undertaken to investigate the arterial calcification in adiponectin-deficient mice in vivo and the effects of adiponectin on cultured vascular smooth muscle cells in vitro. Alizarin red S staining was used to detect arterial calcification of adiponectin(-/-) mice. Alkaline phosphatase activity, osteocalcin secretion, and Runx2 protein expression were examined in cultured calcifying vascular smooth muscle cells (CVSMCs). The involved signal pathway was studied using a mitogen-activated protein kinase (MAPK) inhibitor and adiponectin receptor 1 (AdipoR1) siRNA. Adiponectin(-/-) mice developed slight arterial calcification after being fed with normal chow diet for 30 wk. Adenovirus-mediated supplement of adiponectin attenuated arterial calcification in these mice. On cultured CVSMCs, adiponectin inhibited ALP activity, osteocalcin secretion, Runx2 protein expression, and the formation of mineralized nodules. Adiponectin receptor 1 (AdipoR1) protein was detected in CVSMCs, and adiponectin activated p38 mitogen-activated protein kinase. Furthermore, inhibition of AdipoR1 expression or p38 activation reversed the effects of adiponectin on ALP activity. These results showed that adiponectin inhibited osteoblastic differentiation of CVSMCs through the AdipoR1/p38 signaling pathway. Our findings showed that adiponectin(-/-) mice developed arterial calcification, and this could be attributed to the loss of inhibitory action of adiponectin on osteoblastic differentiation of CVSMCs. It suggested that adiponectin plays a protective role against arterial calcification.
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PMID:Development of arterial calcification in adiponectin-deficient mice: adiponectin regulates arterial calcification. 1925 34

We have recently shown that TNF-related weak inducer of apoptosis (TWEAK) is a mediator of inflammatory bone remodeling. The aim of this study was to investigate the role of TWEAK in modulating human osteoblast activity, and how TWEAK and TNFalpha might interact in this context. Recombinant TWEAK and TNF were both mitogenic for human primary osteoblasts (NHBC). TWEAK dose- and time-dependently regulated the expression of the osteoblast transcription factors RUNX2 and osterix. TWEAK inhibited in vitro mineralization and downregulated the expression of osteogenesis-associated genes. Significantly, TWEAK and TWEAK/TNF induced the expression of the osteoblast differentiation inhibitor and SOST gene product, sclerostin. Sclerostin induction was mitogen-activated protein kinase (MAPK) dependent. The SOST mRNA levels induced by TWEAK were equivalent to or exceeded those seen in steady-state human bone, and the TWEAK/TNF induction of SOST mRNA was recapitulated in fresh cancellous bone explants. TWEAK-induced sclerostin expression was observed in immature osteoblastic cells, both in cycling (Ki67(+)) primary NHBC and in the cell lines MC3T3-E1 and MG-63, as well as in human osteocyte-like cells and in the osteocyte cell line, MLO-Y4. Treatment of NHBC with recombinant human sclerostin mimicked the effects of TWEAK to suppress RUNX2 and osteocalcin (OCN). TWEAK, TNF, and sclerostin treatment of NHBC similarly altered levels of phosphorylated and total GSK3beta and active and total levels of beta-catenin, implying that the Wnt signaling pathway was affected by all three stimuli. Sclerostin also rapidly activated ERK-1/2 MAPK signaling, indicating the involvement of additional signaling pathways. Together, our findings suggest that TWEAK, alone and with TNF, can regulate osteoblast function, at least in part by inducing sclerostin expression. Our results also suggest new roles and modes of action for sclerostin.
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PMID:Pro-inflammatory cytokines TNF-related weak inducer of apoptosis (TWEAK) and TNFalpha induce the mitogen-activated protein kinase (MAPK)-dependent expression of sclerostin in human osteoblasts. 1929 15

Mechanical factors are related to periprosthetic osseointegration following total hip arthroplasty. However, osteoblast response to strain in implanted femurs is unclear because of the absence of accurate stress-measuring methods. In our study, finite element analysis was performed to calculate strain distribution in implanted femurs. 0.8-3.2% tensile strain was then applied to human osteoblasts. Higher magnitudes of strain enhanced the expression of osteocalcin, type I collagen, and Cbfa1/Runx2. Lower magnitudes significantly increased ALP activity. Among these, type I collagen expression increased with the activation of ERK1/2 phosphorylation in a strain-magnitude-dependent manner. Our study marks the first investigation of osteoblast response at different magnitudes of periprosthetic strain. The results indicate that the functional status of human osteoblasts is determined by strain magnitude. The strain distribution in the proximal region of implanted femur should be improved for osseointegration.
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PMID:Different magnitudes of tensile strain induce human osteoblasts differentiation associated with the activation of ERK1/2 phosphorylation. 1933 78

Although substance P (SP) is associated with osteoclast differentiation and bone resorption, little is known about the osteogenic differentiation-inducing effects of SP in periodontal ligament (PDL) cells. This study investigated whether PDL cells could differentiate into osteoblastic-like cells by SP. The expression of osteoblastic differentiation markers such as osteopontin (OPN), osteonectin (ON), osteocalcin (OCN) and bone sialoprotein (BSP) were evaulated by Western blotting. Additionally, SP-mediated heme oxygenase-1 (HO-1) pathways were further clarified. SP increased HO-1 and osteogenic differentiation in concentration- and time-dependent manners, as determined by OPN, ON, OCN and BSP expression. Furthermore, treatment with inhibitors of p38, ERK MAPK, and NF-kappaB abolished SP-induced osteogenic differentiation and HO-1 expression. SP-induced translocation of Nrf-2 was also observed. The combined results suggest that SP activates the stress-response enzymes HO-1 and Nrf-2, subsequently leading to upregulation of osteogenic differentiation in human PDL cells.
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PMID:Effects of substance P on osteoblastic differentiation and heme oxygenase-1 in human periodontal ligament cells. 1935 3


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