title: Warfarin administration disrupts the assembly of mineralized nodules in the osteoid.
abstract: This study aimed to elucidate the ultrastructural role of Gla proteins in bone mineralization by means of a warfarin-administration model. Thirty-six 4-week-old male F344 rats received warfarin (warfarin group) or distilled water (control group), and were fixed after 4, 8 and 12 weeks with an aldehyde solution. Tibiae and femora were employed for histochemical analyses of alkaline phosphatase, osteocalcin and tartrate-resistant acid phosphatase, and for bone histomorphometry and electron microscopy. After 4, 8 and 12 weeks, there were no marked histochemical and histomorphometrical differences between control and warfarin groups. However, osteocalcin immunoreactivity was markedly reduced in the warfarin-administered bone. Mineralized nodules and globular assembly of crystalline particles were seen in the control osteoid. Alternatively, warfarin administration resulted in crystalline particles being dispersed throughout the osteoid without forming mineralized nodules. Immunoelectron microscopy unveiled lower osteocalcin content in the warfarin-administered osteoid, which featured scattered crystalline particles, whereas osteocalcin was abundant on the normally mineralized nodules in the control osteoid. In summary, Gla proteins appear to play a pivotal role in the assembly of mineralized nodules.
authors.affiliation: Center for Transdisciplinary Research, Niigata University, Niigata, Japan. amizuka@dent.niigata-u.ac.jp
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.forename: Minqi
authors.initials: M
authors.lastname: Li
authors.forename: Kuniko
authors.initials: K
authors.lastname: Hara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Paulo H L
authors.initials: PH
authors.lastname: de Freitas
authors.forename: Sobhan
authors.initials: S
authors.lastname: Ubaidus
authors.forename: Kimimitsu
authors.initials: K
authors.lastname: Oda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Akiyama
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects*; D005269:Femur / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D006651:Histocytochemistry; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D016253:Microscopy, Immunoelectron; D015675:Osteocalcin / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014859:Warfarin / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D007527:Isoenzymes; D015675:Osteocalcin; D014859:Warfarin; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase