Plasminogen activator regulation in osteoblasts: Parathyroid hormone inhibition of type‐1 plasminogen activator inhibitor and its mRNA

Fukumoto, Seiji; Allan, Elizabeth; Yee, John A.; Gelehrter, Thomas D.; Martin, T. J.

doi:10.1002/jcp.1041520216

Cited by 37 publications

(24 citation statements)

References 54 publications

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“…With regard to a possible involvement of serine proteinases in bone turnover, plasminogen has been shown to be present in extracellular matrices (Knudsen et al 1986). Furthermore, osteoblasts produce PAs in response to agents that promote bone resorption (Fukumoto et al 1992, Allan & Martin 1995 and most recently it has been suggested that serine proteinases are involved in the degradation of non-collagenous proteins of bone (Daci et al 1999). Although these results support the notion that the PA/plasmin system might be involved in bone resorption, results from other studies suggest a limited role (Leloup et al 1994(Leloup et al , 1996.…”

Section: Introductioncontrasting

confidence: 56%

“…RT-PCR analysis also revealed expression of the serine proteinase inhibitors, PAI-1 and PN-1, in primary mouse osteoblasts. Previous studies have demonstrated that PAI-1 mRNA is decreased in rat osteoblasts by PTH and increased by treatment with transforming growth factor-(TGF-) (Allan et al 1991, Fukumoto et al 1992 thus highlighting the importance of PAI-1 in regulating the PA/plasmin system in rat osteoblasts. Allan and Martin (1995) demonstrated that expression of PAI-2 and PN-1 in rat calvarial osteoblasts was not modulated by prostaglandin E 2 whereas PAI-1 was modulated in a biphasic manner.…”

Section: Discussionmentioning

confidence: 99%

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The effects of serine proteinase inhibitors on bone resorption in vitro

Tumber¹,

Papaioannou²,

Breckon³

et al. 2003

Journal of Endocrinology

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The aims of this study were to identify the role and sites of action of serine proteinases (SPs) in bone resorption, a process which involves a cascade of events, the central step of which is the removal of bone matrix by osteoclasts (OCs). This resorbing activity, however, is also determined by recruitment of new OCs to future resorption sites and removal of the osteoid layer by osteoblasts (OBs), which enables OCs to gain access to the underlying mineralized bone. The resorption systems we have studied consisted of (i) neonatal calvarial explants, (ii) isolated OCs cultured on ivory slices, (iii) mouse OBs cultured on either radiolabelled type I collagen films or bone-like matrix, (iv) bone marrow cultures to assess OC formation and (v) 17-day-old fetal mouse metatarsal bone rudiments to assess OC migration and fusion.Two separate SP inhibitors, aprotinin and 2 -antiplasmin dose-dependently inhibited 45 Ca release from neonatal calvarial explants: aprotinin (10 6 M) was the most effective SP inhibitor, producing a maximum inhibitory effect of 55·9%.Neither of the SP inhibitors influenced either OC formation or OC resorptive activity. In contrast, each SP inhibitor dose-dependently inhibited OB-mediated degradation of both type I collagen fibrils and nonmineralized bone matrix. In 17-day-old metatarsal explants aprotinin produced a 55% reduction in the migration of OCs from the periosteum to the mineralized matrix after 3 days in culture but after 6 days in culture aprotinin was without effect on OC migration. Primary mouse osteoblasts expressed mRNA for urokinase type plasminogen activator (uPA), tissue type plasminogen activator (tPA), the type I receptor for uPA, plasminogen activator inhibitor types I and II and the broad spectrum serine proteinase inhibitor, protease nexin I. In situ hybridization demonstrated expression of tPA and uPA in osteoclasts disaggregated from 6-day-old mouse long bones. We propose that the regulation of these various enzyme systems within bone tissue determines the sites where bone resorption will be initiated.

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Section: Introductioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

The effects of serine proteinase inhibitors on bone resorption in vitro

Tumber¹,

Papaioannou²,

Breckon³

et al. 2003

Journal of Endocrinology

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“…The cyclic nucleotide regulation of PAI-1 mRNA accumulation, first observed in HTC cells (8), has also been demonstrated in rat testicular peritubular cells (58), astrocytes (59) and osteoblasts (60), mink lung epithelial cells (61), human fibrosarcoma cells (62), umbilical vein endothelial cells (63), and synovial cells (64). Our previous experiments have shown that in rat HTC cells, whereas transcriptional regulation plays a role in the cA-induced decrease in PAI-1, the major effect is on message stability.…”

Section: Figmentioning

confidence: 76%

Cyclic Nucleotide Regulation of Type-1 Plasminogen Activator-Inhibitor mRNA Stability in Rat Hepatoma Cells

Heaton

Tillmann-Bogush

Leff

et al. 1998

Journal of Biological Chemistry

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Type-1 plasminogen activator-inhibitor (PAI-1) is a major physiologic inhibitor of plasminogen activation. Incubation of HTC rat hepatoma cells with the cyclic nucleotide analogue, 8-bromo-cAMP, causes a dramatic increase in tissue-type plasminogen activator activity secondary to a 90% decrease in PAI-1 mRNA. Although 8-bromo-cAMP causes a modest decrease in PAI-1 transcription, regulation is primarily the result of a 3-fold increase in the rate of PAI-1 mRNA degradation. To determine the cis-acting sequences required for cyclic nucleotide regulation, we have stably transfected HTC cells with chimeric genes containing sequences from the rat PAI-1 cDNA and the mouse ␤-globin gene and examined the effect of cyclic nucleotides on the decay rate of these transcripts. The mRNA transcribed from the ␤-globin gene is stable and not cyclic nucleotide-regulated, whereas the transcript from a construct containing the ␤-globin coding region and the PAI-1 3-untranslated region (UTR) is destabilized in the presence of 8-bromocAMP, suggesting that this response is mediated by sequences in the PAI-1 3-UTR. Analyses by deletion of sequences from this chimeric construct indicate that, whereas more than one region of the PAI-1 3-UTR can confer cyclic nucleotide responsiveness, the 3-most 134-nucleotide sequence alone is sufficient to do so. Insertion of PAI-1 sequences within the ␤-globin 3-UTR confirms that the 3-most 134 nucleotides of PAI-1 mRNA can confer cyclic nucleotide regulation of stability on a heterologous transcript, suggesting that this sequence may play a major role in hormonal regulation of PAI-1 mRNA stability.Eukaryotic gene expression is determined not only by the rate of gene transcription, but also by the rate at which the transcript is degraded. The steady state concentration of a particular mRNA, as well as the rate at which a new transcriptionally induced steady state is attained, is directly related to the message half-life (1, 2). Numerous recent studies have been aimed at understanding the role of specific sequences within the mRNA in determining basal transcript stability and have led to the identification of consensus sequences that confer stability or instability to a transcript (2, 3). Although it is known that many stimuli alter mRNA stability, little is known about either the cis-acting sequences in the RNA or the cellular factors involved in regulation of message decay.Plasminogen activators (PAs) 1 are serine proteases that are critical for thrombolysis and also play a key role in other physiological functions involving tissue remodeling. Plasminogen activator-inhibitors (PAIs) are specific inhibitors of PAs and are members of the serine protease inhibitor (serpin) family of proteins. Type-1 PAI (PAI-1) is a 50 kDa glycoprotein found in plasma, platelets, and a variety of cell types; its expression is regulated by growth factors, cytokines, and hormones, including agents that alter cellular cAMP levels (4).HTC rat hepatoma cells synthesize and secrete tissue-type plasminogen activator (tPA) and P...

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“…6D shows that, in addition to E4BP4, PTH induces C/EBP␤ binding to EBPRE. PTH inhibits transcription of osteoblastic genes, including both primary (19) and late response genes (20,42,43). The catabolic effects of continuous PTH treatment appear to be associated with decreased expression of many of the genes involved in bone formation and increased expression of genes involved in bone resorption (10).…”

Section: Fig 6 E4bp4 Protein Is Part Of the Pth-induced Binding To mentioning

confidence: 99%

Parathyroid Hormone-induced E4BP4/NFIL3 Down-regulates Transcription in Osteoblasts

Ozkurt

Tetradis

2003

Journal of Biological Chemistry

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Parathyroid hormone (PTH), a major regulator of bone metabolism, activates the PTHR1 receptor on the osteoblast plasma membrane to initiate signaling and induce transcription of primary response genes. Subsequently, primary genes with transcriptional activity regulate expression of downstream PTH targets. We have identified the adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4bp4) as a PTH-induced primary gene in osteoblasts. E4BP4 is a basic leucine zipper (bZIP) transcription factor that represses or activates transcription in non-osteoblastic cells. We report here that PTH rapidly and transiently induced E4bp4 mRNA in osteoblastic cells and that this induction did not require protein synthesis. PTH also induced E4BP4 protein synthesis and E4BP4 binding to a consensus but not to a mutant E4BP4 response element (EBPRE). E4BP4 overexpression inhibited an EB-PRE-containing promoter-reporter construct, whereas PTH treatment attenuated activity of the same construct in primary mouse osteoblasts. Finally, E4BP4 overexpression inhibited PTH-induced activity of a cyclooxygenase-2 promoter-reporter construct. Our data suggest a role for E4BP4 in attenuation of PTH target gene transcription in osteoblasts.

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Plasminogen activator regulation in osteoblasts: Parathyroid hormone inhibition of type‐1 plasminogen activator inhibitor and its mRNA

Cited by 37 publications

References 54 publications

The effects of serine proteinase inhibitors on bone resorption in vitro

The effects of serine proteinase inhibitors on bone resorption in vitro

Cyclic Nucleotide Regulation of Type-1 Plasminogen Activator-Inhibitor mRNA Stability in Rat Hepatoma Cells

Parathyroid Hormone-induced E4BP4/NFIL3 Down-regulates Transcription in Osteoblasts

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