title: Vitamin K catabolite inhibition of ovariectomy-induced bone loss: structure-activity relationship considerations.
abstract: METHODS
  The potential benefit of vitamin K as a therapeutic in osteoporosis is controversial and the vitamin K regimen being used clinically (45 mg/day) employs doses that are many times higher than required to ensure maximal gamma-carboxylation of the vitamin K-dependent bone proteins. We therefore tested the hypothesis that vitamin K catabolites, 5-carbon (CAN5C) and 7-carbon carboxylic acid (CAN7C) aliphatic side-chain derivatives of the naphthoquinone moiety exert an osteotrophic role consistent with the treatment of osteoporosis.
  
  
  RESULTS
  Osteoblast-like MG63 cell cultures were challenged with lipopolysaccharide and the levels of interleukin-6, an osteoclastogenic cytokine, measured with and without catabolites; low concentrations of CAN7C significantly inhibited interleukin-6 release, but CAN5C did not. In models of bone loss induced by ovariectomy or sciatic neurectomy in C57BL/6 mice, we found that the rarer CAN7C catabolite markedly restricted ovariectomy-induced bone loss and possibly limited sciatic neurectomy-induced bone loss. CAN7C activity depends on a free carboxylic acid and its particular side-chain structure.
  
  
  CONCLUSIONS
  These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite.
authors.affiliation: Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Soper
authors.forename: Cenk
authors.initials: C
authors.lastname: Oguz
authors.forename: Roger
authors.initials: R
authors.lastname: Emery
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pitsillides
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Hodges
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002264:Carboxylic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003714:Denervation / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009285:Naphthoquinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D010052:Ovariectomy / Q000009:adverse effects; D011897:Random Allocation; D012584:Sciatic Nerve / Q000601:surgery; D013329:Structure-Activity Relationship; D014812:Vitamin K / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000093242:Interleukin-6 Inhibitors
chemical_list: D050071:Bone Density Conservation Agents; D002264:Carboxylic Acids; D015850:Interleukin-6; D009285:Naphthoquinones; D014812:Vitamin K; D000093242:Interleukin-6 Inhibitors; C000596933:CAN5C compound; C000596929:CAN7C compound; C000596931:CAN8C compound; C508600:IL6 protein, human
keywords: Bone loss; Catabolite; Naphthoquinone; Ovariectomy; Vitamin K