Rats maintained for 8 months on a level of warfarin sufficient to decrease the vitamin K-dependent protein of bone (bone Gla protein) to 2% ofnormal have an excessive mineralization disorder characterized by complete fusion of the proximal tibial growth plate and cessation of longitudinal growth. The general features of this abnormality resemble the fetal warfarin syndrome in humans, a disorder also characterized by excessive mineralization of the growth plate. These excessive mineralization disorders may be caused by the decreased levels of bone Gla protein, a protein that potently inhibits mineralization in vitro.The metabolism of vitamin K presents several intriguing problems in vertebrate physiology and biochemistry. One of the most interesting ofthese is the role ofvitamin K in systems other than blood coagulation. The classical approach to the analysis ofvitamin K physiology has been the study ofdefects in vitamin K-deficient animals. Such studies have established that the first consequence of acute vitamin K deficiency is bleeding and death due to the synthesis of abnormal forms of blood coagulation factors such as prothrombin and factors VII, IX, and X. It is now known that the abnormality in these factors is the absence of 'y-carboxyglutamate (Gla), a Ca2" binding amino acid whose post-translational synthesis from glutamate requires vitamin K (1, 2).Our primary interest over the past several years has been the function of bone Gla protein (BGP), a 49-residue protein of known structure (3, 4) which is numerically one of the 10 most abundant proteins in a typical vertebrate (5,6). To analyze the function ofthis protein in bone metabolism we developed a simple protocol by which rats can be maintained on the vitamin K antagonist warfarin without problems due to bleeding (7). In previous studies we found that animals maintained from birth to 2 months of age on this protocol grow normally and have normal bone structure and mineralization in spite of bone levels of BGP which are only 2% of normal (7).We report here the discovery of excessive mineralization with growth plate closure in the proximal tibia ofrats maintained on warfarin from birth to 8 months of age. MATERIALS AND METHODSMaintenance of Animals on Warfarin. Simonsen albino rats (Sprague-Dawley-derived, Simonsen Laboratories, Gilroy, CA) were maintained from birth to 8 months of age on daily dosages ofwarfarin and vitamin K1 as described (7). To facilitate comparisons, the 10 control rats were selected from litters born at the same time as experimental animals and received daily doses of saline and vitamin K1 (7). Both experimental and control groups had seven male and three female rats. None of the 10 experimental rats chosen at birth for this study showed signs of bleeding or ill health over the 8 months of the experiment. As reported (7), the weight gain ofexperimental and control rats was identical up to 90 days ofage. At8 months ofage the average weights were 402 g for the male and 237 g for the female experimental rats and 455 g for t...

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