Skip to main content
SpringerLink
Log in

Comparison of inhibitory effects of warfarin on γ-carboxylation between bone and liver in rats

  • ORIGINAL ARTICLE
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

Abstract

The purposes of this study were to clarify that warfarin (WF, vitamin K antagonist) levels that inhibit γ-carboxylation are different in liver and bone (experiment 1), and to investigate whether the plasma osteocalcin (OC) level reflects bone OC levels (experiments 2 and 3). Four-week-old male rats were treated with 0.2, 0.4, 0.6, 0.8, 1.0, or 1.2 mg/l of WF solution as drinking water for 4 weeks. Blood coagulation activity, an index of γ-carboxylation of prothrombin in the liver, was significantly decreased in rats receiving 0.8 mg/l or larger doses of WF. A significant decrease of plasma γ-carboxylated OC (GlaOC), an index of γ-carboxylation of OC in bone, was shown in rats receiving 0.2 mg/l or larger doses. Significantly lower OC levels in the femoral diaphysis and metaphysis were shown in the 0.2 mg/l and 0.4 mg/l groups. However, femoral bone mineral density (BMD) values in the WF-treated groups were almost the same as those in the intact group. In experiment 2, we evaluated changes in bone OC levels 4 weeks after discontinuing an 8-week WF treatment. Four-week-old male rats received 0.8 mg/l WF as drinking water for 8 or 12 weeks. Recovery of the OC level after discontinuing the WF treatment was shown in the femoral metaphysis, but not in the diaphysis. In experiment 3, 0.3 mg/kg WF was administrated to 25-week-old male rats three times a week for 8, 12, or 16 weeks. In aged rats, decreased bone OC was shown in the femoral metaphysis, but not in the diaphysis. From these findings, it is suggested that the effects of WF on γ-carboxylation are likely to appear in bone at lower doses than in the liver, that the bone OC level does not always correspond directly to plasma GlaOC, and that the bone OC level is not directly linked with BMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. PV Hauschka JB Lian PM Gallop (1975) ArticleTitleDirect identification of the calcium-binding amino acid, γ-carboxyglutamate, in mineralized tissue Proc Nat Acad Sci U S A 72 3925–3929

    Google Scholar 

  2. PA Price AS Otsuka JW Poser J Kristaponis N Raman (1976) ArticleTitleCharacterization of a γ-carboxyglutamic acid-containing protein from bone Proc Nat Acad Sci U S A 73 1447–1451

    Google Scholar 

  3. PA Price MK Williamson JW Lothringer (1981) ArticleTitleOrigin of the vitamin K-dependent bone protein found in plasma and its clearance by kidney and bone J Biol Chem 256 12760–12766 Occurrence Handle6975778

    PubMed  Google Scholar 

  4. JP Hart MJ Sheare L Klenerman A Catterall J Reeve PN Sambrook RA Dodds L Bitensky J Chayen (1985) ArticleTitleElectrochemical detection of depressed circulating levels of vitamin K1 in osteoporosis J Clin Endocrinol Metab 60 1268–1269 Occurrence Handle3998071

    PubMed  Google Scholar 

  5. SJ Hodges MJ Pilkington TCB Stamp A Catterall MJ Shearer L Bitensky J Chayen (1991) ArticleTitleDepressed levels of circulating menaquinones in patients with osteoporotic fractures of the spine and femoral neck Bone 12 387–389 Occurrence Handle10.1016/8756-3282(91)90027-G Occurrence Handle1797053

    Article  PubMed  Google Scholar 

  6. L Plantalech M Guillaumont P Vergnaud M Leclercq PD Delmas (1991) ArticleTitleImpairment of gamma carboxylation of circulating osteocalcin (bone Gla protein) in elderly women J Bone Miner Res 6 1211–1216 Occurrence Handle1666807

    PubMed  Google Scholar 

  7. P Szulc MC Chapuy PJ Meunier PD Delmas (1993) ArticleTitleSerum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women J Clin Invesf 91 1769–1774

    Google Scholar 

  8. P Szulc M Arlot MC Chapuy F Duboeuf PJ Meunier PD Delmas (1994) ArticleTitleSerum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women J Bone Miner Res 9 1591–1595 Occurrence Handle7817805

    PubMed  Google Scholar 

  9. P Vergnaud P Garnero PJ Meunier G Breart K Kamihagi PD Delmas (1997) ArticleTitleUndercarboxylated osteocalcin measured with a specific immunoassay predicts hip fracture in elderly women: the EPIDOS study J Clin Endocrinol Metab 82 719–724 Occurrence Handle10.1210/jc.82.3.719 Occurrence Handle9062471

    Article  PubMed  Google Scholar 

  10. D Feskanich P Weber WC Willett H Rockett SL Booth GA Colditz (1999) ArticleTitleVitamin K intake and hip fractures in women: a prospective study Am J Clin Nutr 69 74–79 Occurrence Handle9925126

    PubMed  Google Scholar 

  11. SL Booth KL Tucker H Chen MT Hannan DR Gagnon LA Cupples PWF Wilson J Ordovas EJ Schaefer B Dawson-Hughes DP Kiel (2000) ArticleTitleDietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women Am J Clin Nutr 71 1201–1208 Occurrence Handle10799384

    PubMed  Google Scholar 

  12. M Kaneki SJ Hodges T Hosoi S Fujiwara A Lyons ST Crean N Ishida M Nakagawa M Takechi Y Sano Y Mizuno S Hoshino M Miyao S Inoue K Horiki M Shiraki Y Ouchi H Orimo (2001) ArticleTitleJapanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk Nutrition 17 315–321 Occurrence Handle11369171

    PubMed  Google Scholar 

  13. DV Shah JC Swanson JW Suttie (1984) ArticleTitleAbnormal prothrombin in the vitamin K-deficient rat Thromb Res 35 451–458 Occurrence Handle10.1016/0049-3848(84)90236-6 Occurrence Handle6484892

    Article  PubMed  Google Scholar 

  14. JW Poser PA Price (1979) ArticleTitleA method for decarboxylation of γ-carboxyglutamic acid in proteins J Biol Chem 254 431–436 Occurrence Handle762070

    PubMed  Google Scholar 

  15. PA Price Y Kaneda (1987) ArticleTitleVitamin K counteracts the effect of warfarin in liver but not in bone Thromb Res 46 121–131 Occurrence Handle10.1016/0049-3848(87)90212-X Occurrence Handle3495903

    Article  PubMed  Google Scholar 

  16. JW Suttie PC Preusch (1986) ArticleTitleStudies of the vitamin K-dependent carboxylase and vitamin K epoxide reductase in rat liver Haemostasis 16 193–216 Occurrence Handle3530899

    PubMed  Google Scholar 

  17. MMW Ulrich MHJ Knapen MPM Herrmann-Erlee C Vermeer (1988) ArticleTitleVitamin K is no antagonist for the action of warfarin in rat osteosarcoma UMR 106 Thromb Res 50 27–32 Occurrence Handle10.1016/0049-3848(88)90171-5 Occurrence Handle3165226

    Article  PubMed  Google Scholar 

  18. PA Price MK Williamson (1981) ArticleTitleEffects of warfarin on bone J Biol Chem 256 12754–12759 Occurrence Handle6975777

    PubMed  Google Scholar 

  19. JB Lian M Tassinari J Glowacki (1984) ArticleTitleResorption of implanted bone prepared from normal and warfarin-treated rats J Clin Invest 73 1223–1226 Occurrence Handle6608532

    PubMed  Google Scholar 

  20. ES Vesell CA Shively (1974) ArticleTitleLiquid chromatographic assay of warfarin: similarity of warfarin half-lives in human subjects Science 184 466–468 Occurrence Handle4819677

    PubMed  Google Scholar 

  21. P Ducy C Desbois B Boyce G Pinero B Story C Dunstan E Smith J Bonadio S Goldstein C Gundberg A Bradley G Karsenty (1996) ArticleTitleIncreased bone formation in osteocalcin-deficient mice Nature 382 448–452 Occurrence Handle10.1038/382448a0 Occurrence Handle8684484

    Article  PubMed  Google Scholar 

  22. A Haffa D Krueger J Bruner J Engelke C Gundberg M Akhter N Binkley (2000) ArticleTitleDiet- or warfarin-induced vitamin K insufficiency elevates circulating undercarboxylated osteocalclin without altering skeletal status in growing female rats J Bone Miner Res 15 872–878 Occurrence Handle10804016

    PubMed  Google Scholar 

  23. AL Boskey S Gadaleta C Gundberg SB Doty P Ducy G Karsenty (1998) ArticleTitleFourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into function of osteocalcin Bone 23 187–196 Occurrence Handle10.1016/S8756-3282(98)00092-1 Occurrence Handle9737340

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Applied Drug Research, Pharmacological Evaluation Section, Clinical Research Center, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, 112-8088, Japan

    Kuniko Hara, Masatoshi Kobayashi & Yasuhiro Akiyama

Authors
  1. Kuniko Hara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masatoshi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yasuhiro Akiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kuniko Hara.

About this article

Cite this article

Hara, K., Kobayashi, M. & Akiyama, Y. Comparison of inhibitory effects of warfarin on γ-carboxylation between bone and liver in rats. J Bone Miner Metab 23, 366–372 (2005). https://doi.org/10.1007/s00774-005-0614-7

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-005-0614-7

Key words

Search

Navigation