Abstract
The development of osteoporosis involves the interaction of multiple environmental and genetic factors. Through combined genetic and genomic approaches, we identified the lipoxygenase gene Alox15 as a negative regulator of peak bone mineral density in mice. Crossbreeding experiments with Alox15 knockout mice confirmed that 12/15-lipoxygenase plays a role in skeletal development. Pharmacologic inhibitors of this enzyme improved bone density and strength in two rodent models of osteoporosis. These results suggest that drugs targeting the 12/15-lipoxygenase pathway merit investigation as a therapy for osteoporosis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Arachidonate 12-Lipoxygenase / genetics*
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Arachidonate 12-Lipoxygenase / metabolism*
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Arachidonate 15-Lipoxygenase / genetics*
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Arachidonate 15-Lipoxygenase / metabolism*
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Bone Density / drug effects
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Bone Density / genetics*
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Bone Marrow Cells / metabolism
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Cell Differentiation
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Cells, Cultured
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Crosses, Genetic
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Enzyme Inhibitors / pharmacology
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Female
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Fluorenes / pharmacology
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Gene Expression Profiling
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Genetic Linkage
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Kidney / metabolism
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Lipoxygenase Inhibitors
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Inbred Strains
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Mice, Knockout
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Mice, Transgenic
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Oligonucleotide Array Sequence Analysis
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Osteoblasts / cytology
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Osteoblasts / metabolism
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Osteoblasts / physiology
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Osteogenesis
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Osteoporosis / enzymology
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Polymorphism, Genetic
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Quantitative Trait Loci
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Rats
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Receptors, Cytoplasmic and Nuclear / metabolism
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Stromal Cells / metabolism
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Transcription Factors / metabolism
Substances
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12-15-lipoxygenase
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6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
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Enzyme Inhibitors
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Fluorenes
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Lipoxygenase Inhibitors
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Receptors, Cytoplasmic and Nuclear
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Transcription Factors
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Arachidonate 12-Lipoxygenase
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Arachidonate 15-Lipoxygenase