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.
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Authors | Robert F Klein, John Allard, Zafrira Avnur, Tania Nikolcheva, David Rotstein, Amy S Carlos, Marie Shea, Ruth V Waters, John K Belknap, Gary Peltz, Eric S Orwoll |
Journal | Science (New York, N.Y.)
(Science)
Vol. 303
Issue 5655
Pg. 229-32
(Jan 09 2004)
ISSN: 1095-9203 [Electronic] United States |
PMID | 14716014
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- 12-15-lipoxygenase
- 6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene
- Enzyme Inhibitors
- Fluorenes
- Lipoxygenase Inhibitors
- Receptors, Cytoplasmic and Nuclear
- Transcription Factors
- Arachidonate 12-Lipoxygenase
- Arachidonate 15-Lipoxygenase
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Topics |
- Animals
- Arachidonate 12-Lipoxygenase
(genetics, metabolism)
- Arachidonate 15-Lipoxygenase
(genetics, metabolism)
- Bone Density
(drug effects, genetics)
- Bone Marrow Cells
(metabolism)
- Cell Differentiation
- Cells, Cultured
- Crosses, Genetic
- Enzyme Inhibitors
(pharmacology)
- Female
- Fluorenes
(pharmacology)
- Gene Expression Profiling
- Genetic Linkage
- Kidney
(metabolism)
- Lipoxygenase Inhibitors
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred Strains
- Mice, Knockout
- Mice, Transgenic
- Oligonucleotide Array Sequence Analysis
- Osteoblasts
(cytology, metabolism, physiology)
- Osteogenesis
- Osteoporosis
(enzymology)
- Polymorphism, Genetic
- Quantitative Trait Loci
- Rats
- Receptors, Cytoplasmic and Nuclear
(metabolism)
- Stromal Cells
(metabolism)
- Transcription Factors
(metabolism)
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