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Mol Nutr Food Res ; 58(8): 1658-66, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25044634

ABSTRACT

SCOPE: 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. METHODS AND 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. CONCLUSION: These in vivo data indicate for the first time that the clinical utility of vitamin K for osteoporosis may reside in an unusual catabolite.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Carboxylic Acids/therapeutic use , Disease Models, Animal , Naphthoquinones/therapeutic use , Osteoporosis, Postmenopausal/drug therapy , Vitamin K/analogs & derivatives , Animals , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacology , Carboxylic Acids/administration & dosage , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Line , Cell Proliferation/drug effects , Denervation/adverse effects , Female , Humans , Injections, Intraperitoneal , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Methylation , Mice, Inbred C57BL , Molecular Structure , Naphthoquinones/administration & dosage , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Osteoblasts/cytology , Osteoblasts/drug effects , Osteoblasts/metabolism , Ovariectomy/adverse effects , Random Allocation , Sciatic Nerve/surgery , Structure-Activity Relationship , Vitamin K/administration & dosage , Vitamin K/pharmacology , Vitamin K/therapeutic use
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