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Science 9 January 2004:
Vol. 303. no. 5655, pp. 229 - 232
DOI: 10.1126/science.1090985
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Reports

Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox15

Robert F. Klein,1,4* John Allard,5 Zafrira Avnur,5 Tania Nikolcheva,5 David Rotstein,6 Amy S. Carlos,1,4 Marie Shea,2 Ruth V. Waters,5 John K. Belknap,3,4 Gary Peltz,5 Eric S. Orwoll1,4

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.

1 Bone and Mineral Research Unit, Department of Medicine, School of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
2 Department of Orthopaedics and Rehabilitation, School of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
3 Department of Behavioral Neuroscience, School of Medicine, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA.
4 Veterans Affairs Medical Center, 3710 Southwest U.S. Veterans Hospital Road, Portland, OR 97207, USA.
5 Department of Genetics and Genomics, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA.
6 Department of Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94303, USA.

* To whom correspondence should be addressed: e-mail: kleinro{at}ohsu.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)