Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox15

• Published in: Science (American Association for the Advancement of Science) 2004-01, Vol.303 (5655), p.229-232
• Main Authors: Klein, Robert F., Allard, John, Avnur, Zafrira, Nikolcheva, Tania, Rotstein, David, Carlos, Amy S., Shea, Marie, Waters, Ruth V., Belknap, John K., Peltz, Gary, Orwoll, Eric S.
• Format: Article
• Language: English
• Subjects: 12-15-lipoxygenase; Alleles; Alox15 gene; Animals; Arachidonate 12-Lipoxygenase - genetics; Arachidonate 12-Lipoxygenase - metabolism; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Biological and medical sciences; Body Weight; Bone density; Bone Density - drug effects; Bone Density - genetics; Bone Marrow Cells - metabolism; Bones; Cell Differentiation; Cells, Cultured; Chemical properties; Chromosomes; Crosses, Genetic; Density; Diseases of the osteoarticular system; Environmental Influences; Enzyme Inhibitors - pharmacology; Female; Fluorenes - pharmacology; Gene Expression Profiling; Gene expression regulation; Genes; Genetic aspects; Genetic Linkage; Genetics; House mouse; Individualized Instruction; Kidney - metabolism; Kidneys; Lipoxygenase Inhibitors; Male; Medical sciences; Mice; Mice as laboratory animals; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Mice, Transgenic; Oligonucleotide Array Sequence Analysis; Osteoblasts - cytology; Osteoblasts - metabolism; Osteoblasts - physiology; Osteogenesis; Osteoporosis; Osteoporosis - enzymology; Osteoporosis. Osteomalacia. Paget disease; Physiological aspects; Polymorphism, Genetic; Quantitative Trait Loci; Rats; Receptors, Cytoplasmic and Nuclear - metabolism; Rodents; Scientific Concepts; Skeletal development; Statistical Analysis; Stromal Cells - metabolism; Transcription Factors - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1090985

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.