Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to determine the mechanism by which parathyroid hormone (PTH) stimulates plasminogen activator (PA) activity in rat osteoblasts, we investigated the effect of human PTH(1-34) [hPTH(1-34)] on the synthesis of mRNAs for tissue-type PA (tPA), urokinase-type PA (uPA), and PA inhibitor-1 (PAI-1), and on release of PA activity and PAI-1 protein in both normal rat calvarial osteoblasts and UMR 106-01 osteogenic sarcoma cells. hPTH(1-34) (0.25-25 nM) decreased PAI-1 mRNA and protein, and increased PA activity in both cell types in a dose-dependent manner with ED50 of about 1 nM for both responses. Forskolin and isobutylmethylxanthine also stimulated PA activity and decreased PAI-1 protein and mRNA in both cell types. hPTH(1-34) did not show any consistent effect on tPA and uPA mRNA in calvarial osteoblasts, but a modest (two-fold) increase of both mRNAs was observed in UMR 106-01 cells treated with 25 nM hPTH(1-34). However, when protein synthesis was inhibited with 100 microM cycloheximide, the increase of tPA and uPA mRNA by hPTH(1-34) was enhanced in UMR 106-01 cells and became evident in calvarial osteoblasts. Fibrin autography also revealed that hPTH(1-34) increases tPA and uPA activity, especially after cycloheximide treatment in UMR 106-01 cells. These results strongly suggest that PTH increases PA activity predominantly by decreasing PAI-1 protein production through a cyclic adenosine monophosphate (cAMP)-dependent mechanism in rat osteoblasts. The reduction of PAI-1 protein by PTH results in enhanced action of both tPA and uPA, and would contribute to the specific roles of these PAs in bone.
 ...
PMID:Plasminogen activator regulation in osteoblasts: parathyroid hormone inhibition of type-1 plasminogen activator inhibitor and its mRNA. 132 17

The identification of the plasminogen activator (PA) types present in bone and the regulation of their activity by parathyroid hormone (PTH) were investigated in cultures of fetal mouse calvariae with the use of either a chromogenic substrate or a zymographic assay. PA was detected essentially in the tissue extracts of the explanted bones, with only 1-2% of the total activity released in the surrounding culture media. From their electrophoretic behavior compared to PAs of other mouse tissues and from their response to a specific antibody raised against the tissue type PA (tPA), two major molecular species, of 70 and 48 kD were identified as tPA and urokinase (uPA), respectively, a third minor species of 105 kD being likely to correspond to complexes between tPA and an inhibitor; the culture fluids, moreover, contained enzymatically active degradation products of uPA of 42 and 29 kD. The PA activity of the bone extracts was only minimally affected by the addition of fibrinogen fragments to the chromogenic assays. PTH induced bone resorption and stimulated in parallel the accumulation of PA in the tissue; other bone-resorbing agents, 1,25-dihydroxyvitamin D3 and prostaglandin E2, had similar effects. Densitometric scanning of the zymograms of the bone extracts indicated that PTH stimulated only the production of tPA and had no effect on that of uPA. However, PTH also enhanced the release of uPA (both the 48 kD and the 29 kD forms) from the bones into the media. Although inhibiting bone resorption, calcitonin had no effect on the PTH-induced accumulation of PA in bone or on the release of tPA, but it prevented the PTH-induced accumulation of 29 kD uPA in the culture fluids. Thus these studies support the view that tPA and possibly also uPA may have a role in the physiology of bone; the nature of this role remains to be elucidated, however.
 ...
PMID:Tissue and urokinase plasminogen activators in bone tissue and their regulation by parathyroid hormone. 179 56

In rat calvarial osteoblast-like cells and in clonal osteogenic sarcoma cells (UMR 106-01), 1,25-dihydroxyvitamin D-3 (1,25(OH)2D3) enhanced plasminogen activator (PA) activity and decreased PA inhibitor-1 (PAI-1) production over the same concentration range. Steady-state levels of mRNA for PAI-1 were also decreased by 1,25(OH)2D3 in a dose-dependent manner, without significant effects on mRNA for either tissue-type PA (tPA) or urokinase-type PA (uPA). When protein synthesis was inhibited by cycloheximide treatment in UMR 106-01 cells, the action of 1,25(OH)2D3 on PAI-1 mRNA was abolished, as was observed previously with parathyroid hormone (PTH) treatment. In osteoblast-like cells however, 1,25(OH)2D3 and PTH actions differed, in that 1,25(OH)2D3 had no effect on either PAI-1 or uPA mRNA levels under conditions of protein synthesis inhibition, whereas PTH decreased PAI-1, and increased uPA mRNA. Identification of proteins involved in these actions may help to explain differences in molecular regulation by PTH and 1,25(OH)2D3, two agents which have similar actions on osteoblasts, but employ different signal transduction pathways.
 ...
PMID:Regulation of plasminogen activator inhibitor-1 (PAI-1) expression by 1,25-dihydroxyvitamin D-3 in normal and malignant rat osteoblasts. 794 35

An attempt was made to establish whether the activation of plasminogen into plasmin is necessary either for the preparatory phases to bone resorption, involving the recruitment of osteoclast precursors, their migration toward mineralized surfaces, and their final differentiation, or for the subsequent osteoclastic resorption phase. 45Ca-labeled fetal (17 day) mouse metatarsals were cultured under conditions in which they pursue their modeling for a few days. In this model, the resorption phase, monitored by the release of 45Ca into the medium, is entirely dependent on the preparatory phases affecting osteoclast precursors. It was, as expected, stimulated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3 and inhibited by calcitonin. PTH also enhanced the activity of tissue-type plasminogen activator (PA) in extracts of metatarsals but not that of urokinase (which is, however, the main PA present in the mouse fetal metatarsal culture model). The resorption processes were not dependent on the presence of plasminogen in the media, even when the rudiments were precultured with tranexamic acid to remove their endogenous plasminogen. Moreover, they were not influenced by inhibitors of plasmin, either the plasma inhibitors alpha 2-antiplasmin, alpha 2-macroglobulin, and alpha 1-antitrypsin, or aprotinin, which was tested under a variety of conditions. Aprotinin also did not influence the resorption (loss of calcium and hydroxyproline) of 19 day fetal mouse calvariae cultured with PTH in a medium devoid of plasminogen. It is concluded that the various steps implicated in the bone resorption processes that occur in the metatarsals and in the calvariae culture models are not dependent on the activity of plasmin. The function of PAs in bone, however, could be exerted through direct proteolysis of extracellular proteins other than plasminogen or be mediated by a molecular structural domain distinct from their catalytic domain.
 ...
PMID:Relationship of the plasminogen activator/plasmin cascade to osteoclast invasion and mineral resorption in explanted fetal metatarsal bones. 807 64

8701-BC is a recently characterized cell line isolated from a primary ductal infiltrating carcinoma of the breast (d.i.c.), showing some pleomorphism in cell microanatomy at an ultrastructural level. We have obtained different sublines of 8701-BC cells by cloning in soft agar at different concentrations (0.3% and 0.6%), and we have characterized the cloned lines by some morphological and growth parameters. 8701-BC cells and clones have been submitted to analysis by reverse transcriptase-linked polymerase chain reaction to detect mRNAs of various cytokines (transforming growth factor-beta s, tumour necrosis factors, interleukin 1s, interleukin 6, parathyroid hormone-related peptide, gamma interferon) and of urokinase, which are bioactive molecules commonly involved in cell-cell and cell-stroma interactions at primary and/or secondary sites of invasion. The aims of the present investigation were to determine: (a) if the corresponding genes are active in 8701-BC cell line and (b) if the sublines tested exhibit transcriptional heterogeneity. The results obtained show that 8701-BC cells express transcripts of transforming growth factor-beta s, urokinase and parathyroid hormone-related peptide (PTHrP), the latter product being responsible for the cancer-associated humoral hypercalcemic syndrome. Moreover, while the first two mRNAs are detectable in all the sublines tested, PTHrP is expressed almost uniquely by the clones isolated in 0.6% agar which exhibit a peculiar morphological appearance, a higher growth rate and a more active invasive behaviour in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Transforming growth factor-beta 1, beta 2, and beta 3, urokinase and parathyroid hormone-related peptide expression in 8701-BC breast cancer cells and clones. 829 80

Plasminogen activators (PA) are implicated in cell migration and tissue remodeling, two components of the bone resorption processes. Using mice with inactivated tissue PA (tPA), urokinase PA (uPA), or type 1 PA inhibitor (PAI-1) genes, we evaluated whether these processes, or their stimulation by parathyroid hormone (PTH) or 1,25-dihydroxyvitamin (1,25[OH]2D3) are dependent on these genes. Two culture models were used, one involving 19-day fetal calvariae, to evaluate the direct resorptive activity of osteoclasis, and the other involving 45Ca-labeled 17-day fetal metatarsals, in which this activity depends on preliminary (pre)osteoclast migration. PTH similarly increased (about 10-fold) PA activity in calvariae from wild-type tPA+/+ and uPA+/+ or deficient uPA-/- and PAI-/- mice; it affected only tPA, not uPA. In tPA-/- bones, the low PA levels, due to uPA, were not influenced by PTH. Calcitonin did not affect PA responses to PTH. No differences were observed between tPA+/+, tPA-/-, uPA+/+, and uPA-/- calvariae for any parameter related to bone resorption (development of lacunae, release of calcium and lysosomal enzymes, accumulation of collagenase, loss of hydroxyproline), indicating similar responses to PTH or calcitonin. The progressive 45Ca release was largely similar in cultures of tPA+/+, tPA-/-, uPA+/+, uPA-/-, PAI+/+, or PAI-/- metatarsals and it was similarly enhanced by PTH or 1,25(OH)2D3. However, uPA-/- metatarsals released 45Ca at a slower rate at the beginning of the cultures, suggesting an impaired recruitment of the (pre)osteoclasts, which migrate at that time from the periosteum into the calcified cartilage. Thus, it appears that the direct resorptive activity of the osteoclasts does not necessitate the presence of either tPA or uPA, but uPA is likely to facilitate the migration of the (pre)osteoclasts toward the mineralized surfaces. Although considerably enhanced by PTH, tPA does not mediate the actions of PTH (nor of 1,25[OH]2D3) evaluated in these models.
 ...
PMID:Bone resorption and response to calcium-regulating hormones in the absence of tissue or urokinase plasminogen activator or of their type 1 inhibitor. 885 51

Although several neoplasms may produce osteoblastic metastases, carcinoma of the prostate is by far the most common. Biochemical and histologic studies indicate that osteolysis also is a manifestation of prostate carcinoma. Furthermore, factors such as parathyroid hormone-related peptide, which mediate osteolysis in other cancers, also appear to be operative in the bone breakdown induced by prostate carcinoma. However, the most unique skeletal effect of this tumor is its consistent capacity to stimulate osteoblasts to deposit new bone. Several bone growth factors have been detected in prostatic tissue and may contribute to this process. These include transforming growth factor-beta, fibroblast growth factor, and bone morphogenetic proteins. The author isolated an amino-terminal fragment (ATF) of the protease urokinase (uPA) from the conditioned medium of the prostate carcinoma cell line PC-3 and demonstrated that this fragment has mitogenic activity for osteoblastic cells. The activity appears to reside in an epidermal growth factor-like growth factor domain (GFD) within the ATF. Subsequently, the author cloned the rat uPA receptor (uPAR). uPAR is known to bind the ATF and can permit the uPA molecule to exhibit focal proteolysis. It was shown that the ATF also can induce c-myc, c-jun, and c-fos in osteoblastic cells. This effect of ATF can be mimicked by the GFD and suggests that this signalling pathway in osteoblasts is via the uPAR. Consequently, the uPA molecule may contribute to growth factor effects in osteoblasts via the NH2-terminal fragment and to tumor invasiveness via its COOH-terminal proteolytic domain. This scenario is supported by results from studies with uPA-overexpressing prostate carcinoma cells in rats. Additional studies will be required to further define the mechanisms of interaction of prostate carcinoma and other cancers with bone but each site of molecular interaction may provide a therapeutic window for curtailing the effects of these tumors on the skeleton.
 ...
PMID:Mechanisms of the development of osteoblastic metastases. 936 25

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abarelix, ABX-EGF, ademetionine, agomelatine, AMGN-0007, 9-aminocamptothecin, AN-9, anecortave acetate, anidulafungin, AOD-9604, apolizumab, apomate, L-arginine hydrochloride, arzoxifene hydrochloride; Bevacizumab, BP-897, BufferGel; Capravirine, carboxyamidotriazole, carnosine, CC-4047, CEP-701, cerivastatin sodium, clofarabine, conivaptan hydrochloride, CP-461, CS-003; Daptomycin, darifenacin, decitabine, deferasirox, duloxetine hydrochloride; Eberconazole, Ecyd, efalizumab, eglumegad hydrate, EMD-72000, (-)-epigallocatechin gallate, exatecan mesilate, exenatide; Fampridine, fenretinide, ferumoxtran-10; Gadofosveset sodium, garenoxacin mesilate, genistein, glutamine, GPI-15715; Hexyl insulin M2, human insulin, HYB-165; Indisulam, irofulven; KRN-5500, L-796568, laurocapram, lidocaine/prilocaine, lonafarnib, lotrafiban; Melagatran, melatonin, 2-methoxyestradiol, metreleptin, motexafin gadoliniu, motexafin lutetium; Natalizumab, nelarabine, NO-aspirin, NSC-683864; ONO-6126; Pemetrexed disodium, pexelizumab, pirfenidone, PncCRM9, polyglutamate paclitaxel, pramlintide acetate pregabalin, PRO-2000; Ragaglitazar, ramelteon, rasagiline mesilate, rDNA insulin, recombinant glucagon-like peptide-1 (7-36) amide, recombinant human parathyroid hormone (1-84), reolysin RG228, roflumilast, roxifiban acetate, RPI-4610, rubitecan; Safinamide mesilate, solifenacin succinate, SRL-172; T-138067, tafenoquine succinate, tecadenoson, TER-286, tesaglitazar, tetrathiomolybdate, tezosentan disodium, TheraCIM, tigecycline, tipifarnib, tolvaptan, trabectedin, tributyrin, trimegestone, troxacitabine; UCN-01, urokinase alfa; Vinflunine, viscum fraxini 2; Xcellerated T cells, ximelagatran.
 ...
PMID:Gateways to clinical trials. 1468 3