Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata

Pauli, Richard M.; Madden, John D.; Jeffery^Kranzler, K.; Culpepper, Walter S.; Ronald, Port

doi:10.1016/s0022-3476(76)80281-8

Cited by 68 publications

(16 citation statements)

References 8 publications

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“…Both doses of warfarin, however, had no significant effect on the MGP. DISCUSSION Investigations into the physiologic function of osteocalcin have focused on bone metabolism in warfarintreated or vitamin K-deficient animals (Krauss et al, 1949;Hirsh et al, 1970;Kronick et al, 1974) or pa- tients (Pauli et al, 1976;Hall et al, 1980;IturbeAlessio et al, 1986;Rutherford and Phelan, 1986;Menon et al, 1987). Since the activity of the Gla residues is a key component to the functional properties of osteocalcin and MGP, we have investigated the inhibition of Gla synthesis in these proteins by warfarin in experimental systems where osteocalcin and MGP are expressed during the development of bone and cartilage tissues in vivo and in vitro.…”

Section: Mgp Expression In Warfarin-treated Chondrocyte Culturesmentioning

confidence: 99%

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix Gla protein in vitro

Barone

Aronow

Tassinari

et al. 1994

Journal Cellular Physiology

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The role of the vitamin K dependent proteins, osteocalcin which is bone specific and matrix Gla protein (MGP) found in many tissues, has been studied by inhibition of synthesis of their characteristic amino acid, gamma-carboxyglutamic acid (Gla) with the anticoagulant sodium warfarin. The effect of sodium warfarin on expression of these proteins, and other phenotypic markers of bone and cartilage during cellular differentiation and development of tissue extracellular matrix, was examined in several model systems. Parameters assayed include cell growth (reflected by histone gene expression) and collagen types I and II, osteopontin, alkaline phosphatase, and mineralization. Studies were carried out in calvarial bone organ cultures, normal diploid rat osteoblast and chondrocyte cultures, and rat osteosarcoma cell lines ROS 17/2.8 and 25/1. In normal diploid cells, warfarin consistently stimulated cell proliferation (twofold). In osteoblast cultures, MGP mRNA levels were generally increased (three to tenfold). Notably, MGP mRNA levels were not affected in chondrocyte cultures, either with chronic or acute warfarin treatments. Osteocalcin mRNA levels and synthesis were decreased up to 50% in ROS 17/2.8 cells and in chronically treated (1 and 5 micrograms/ml sodium warfarin) rat osteoblast cultures after 22 days. Early stages of osteoblast phenotype development from the proliferation period to initial tissue formation (nodules) appeared unaffected; while after day 14, further growth and mineralization of the nodule areas were significantly decreased in warfarin-treated cultures. In summary, warfarin has opposing effects on the expression of two vitamin K dependent proteins, MGP and osteocalcin, in osteoblast cultures and MGP is regulated differently between cartilage and bone as reflected by cellular mRNA levels. Additionally, warfarin effects expression of nonvitamin K dependent proteins which may reflect the influence of warfarin on endoplasmic reticulum associated enzymes.

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Section: Mgp Expression In Warfarin-treated Chondrocyte Culturesmentioning

confidence: 99%

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix Gla protein in vitro

Barone

Aronow

Tassinari

et al. 1994

Journal Cellular Physiology

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“…Concern about fetal malformations secondary to maternal coumadin therapy has focused on a syndrome of nasal hypoplasia, chondrodysplasia, and stippled epiphyses of bone (chrondrodysplasia punctata) (188)(189)(190)(191). Other findings may include mental retardation, hypertelorism, and a variety of other skeletal abnormalities.…”

Section: Pulmonary Embolismmentioning

confidence: 99%

“…Other findings may include mental retardation, hypertelorism, and a variety of other skeletal abnormalities. At least 8 cases of this syndrome have now been reported with associated maternal use of warfarin (191).…”

Section: Pulmonary Embolismmentioning

confidence: 99%

Pregnancy and The Lung^1,²

Se¹,

St²,

Cohen³

et al. 1980

Am Rev Respir Dis

305

110

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“…Developmental activities for these VKDPs have been hypothesized 11 based on the human teratogenic effects of warfarin, a pharmacological inhibitor of Gla synthesis. 12,13 Developmental functions for Gla-containing VKDPs also have been suggested by data developed in a chick embryogenesis model, 14 in which vitamin K-dependent signaling events appear to be critical for orderly embryogenesis. Furthermore, mice unable to synthesize Gla due to targeted disruption of the carboxylase gene experience fetal demise or developmental abnormalities with features that resemble the human warfarin embryopathy syndrome, 15 indicating that Gla synthesis is essential during mammalian development.…”

Section: Introductionmentioning

confidence: 90%

The vitamin K–dependent γ-glutamyl carboxylase gene contains a TATA-less promoter with a novel upstream regulatory element

Romero

Marvi

Niman

2003

Blood

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The expression of the vitamin K-dependent ␥-glutamyl carboxylase gene in liver is developmentally regulated. Since the gene product catalyzes an essential posttranslational modification of the vitamin K-dependent blood coagulation proteins, the regulation of carboxylase expression is critical for hemostasis. We analyzed the activity of the rat carboxylase gene 5-regulatory DNA sequences in rat hepatoma cell lines at different states of differentiation. These studies demonstrated that the 2.6-kb 5-flanking sequence has differentiation-dependent transcriptional activity. Transient gene expression assays, examining the effects of nested deletions and site-directed mutagenesis of putative regulatory sequences, together with electrophoretic mobility shift assays (EMSAs) were used to identify sequences critical for the developmentally regulated transcription of the rat carboxylase gene. We identified a DNA sequence (؊76 to ؊65; GTTCCGGCCTTC) not known to bind to transcription factors, yet which functions as an upstream promoter element. In vivo genomic DNA footprinting confirms the presence of

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Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata

Cited by 68 publications

References 8 publications

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix Gla protein in vitro

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix Gla protein in vitro

Pregnancy and The Lung^1,²

The vitamin K–dependent γ-glutamyl carboxylase gene contains a TATA-less promoter with a novel upstream regulatory element

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Warfarin therapy initiated during pregnancy and phenotypic chondrodysplasia punctata

Cited by 68 publications

References 8 publications

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix Gla protein in vitro

Differential effects of warfarin on mRNA levels of developmentally regulated vitamin K dependent proteins, osteocalcin, and matrix Gla protein in vitro

Pregnancy and The Lung1,2

The vitamin K–dependent γ-glutamyl carboxylase gene contains a TATA-less promoter with a novel upstream regulatory element

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Pregnancy and The Lung^1,²