Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 9 January 2004:
Vol. 303. no. 5655, pp. 229 - 232
DOI: 10.1126/science.1090985
Prev | Table of Contents | Next

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

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Increased Lipid Oxidation Causes Oxidative Stress, Increased Peroxisome Proliferator-activated Receptor-{gamma} Expression, and Diminished Pro-osteogenic Wnt Signaling in the Skeleton.
M. Almeida, E. Ambrogini, L. Han, S. C. Manolagas, and R. L. Jilka (2009)
J. Biol. Chem. 284, 27438-27448
   Abstract »    Full Text »    PDF »
Quantitative trait loci for biomechanical performance and femoral geometry in an intercross of recombinant congenic mice: restriction of the Bmd7 candidate interval.
N. Saless, S. J. Litscher, G. E. L. Franco, M. J. Houlihan, S. Sudhakaran, K. A. Raheem, T. K. O'Neil, R. Vanderby, P. Demant, and R. D. Blank (2009)
FASEB J 23, 2142-2154
   Abstract »    Full Text »    PDF »
The Future of Mouse Genetics in Osteoporosis Research.
C. L. Ackert-Bicknell and C. J. Rosen (2009)
IBMS BoneKEy 6, 200-209
   Abstract »    Full Text »    PDF »
De-fense! De-fense! De-fense: Scavenging H2O2 While Making Cholesterol.
S. C. Manolagas (2008)
Endocrinology 149, 3264-3266
   Full Text »    PDF »
The cell biology of bone metabolism.
H K Datta, W F Ng, J A Walker, S P Tuck, and S S Varanasi (2008)
J. Clin. Pathol. 61, 577-587
   Abstract »    Full Text »    PDF »
Candidate genes controlling pulmonary function in mice: transcript profiling and predicted protein structure.
K. Ganguly, T. Stoeger, S. C. Wesselkamper, C. Reinhard, M. A. Sartor, M. Medvedovic, C. R. Tomlinson, I. Bolle, J. M. Mason, G. D. Leikauf, et al. (2007)
Physiol Genomics 31, 410-421
   Abstract »    Full Text »    PDF »
Molecular Genetic Analysis of Two Loci (Ity2 and Ity3) Involved in the Host Response to Infection With Salmonella Typhimurium Using Congenic Mice and Expression Profiling.
V. Sancho-Shimizu, R. Khan, S. Mostowy, L. Lariviere, R. Wilkinson, N. Riendeau, M. Behr, and D. Malo (2007)
Genetics 177, 1125-1139
   Abstract »    Full Text »    PDF »
Skeletal Involution by Age-associated Oxidative Stress and Its Acceleration by Loss of Sex Steroids.
M. Almeida, L. Han, M. Martin-Millan, L. I. Plotkin, S. A. Stewart, P. K. Roberson, S. Kousteni, C. A. O'Brien, T. Bellido, A. M. Parfitt, et al. (2007)
J. Biol. Chem. 282, 27285-27297
   Abstract »    Full Text »    PDF »
Mouse Chromosome 7 Harbors a Quantitative Trait Locus for Isoflurane Minimum Alveolar Concentration.
M. Cascio, Y. Xing, D. Gong, J. Popovich, E. I. Eger II, S. Sen, G. Peltz, and J. M. Sonner (2007)
Anesth. Analg. 105, 381-385
   Abstract »    Full Text »    PDF »
Interdependence of lipoxin A4 and heme-oxygenase in counter-regulating inflammation during corneal wound healing.
B. Biteman, I. R. Hassan, E. Walker, A. J. Leedom, M. Dunn, F. Seta, M. Laniado-Schwartzman, and K. Gronert (2007)
FASEB J 21, 2257-2266
   Abstract »    Full Text »    PDF »
Lack of Schnurri-2 Expression Associates with Reduced Bone Remodeling and Osteopenia.
Y. Saita, T. Takagi, K. Kitahara, M. Usui, K. Miyazono, Y. Ezura, K. Nakashima, H. Kurosawa, S. Ishii, and M. Noda (2007)
J. Biol. Chem. 282, 12907-12915
   Abstract »    Full Text »    PDF »
Fine Mapping Reveals Sex Bias in Quantitative Trait Loci Affecting Growth, Skeletal Size and Obesity-Related Traits on Mouse Chromosomes 2 and 11.
C. R. Farber and J. F. Medrano (2007)
Genetics 175, 349-360
   Abstract »    Full Text »    PDF »
Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease.
M. K. Middleton, A. M. Zukas, T. Rubinstein, M. Jacob, P. Zhu, L. Zhao, I. Blair, and E. Pure (2006)
J. Exp. Med. 203, 2529-2540
   Abstract »    Full Text »    PDF »
Genetic regulation of bone mass and susceptibility to osteoporosis.
S. H. Ralston and B. de Crombrugghe (2006)
Genes & Dev. 20, 2492-2506
   Abstract »    Full Text »    PDF »
Monocyte 15-Lipoxygenase Expression Is Regulated by a Novel Cytosolic Signaling Complex with Protein Kinase C {delta} and Tyrosine-Phosphorylated Stat3.
A. Bhattacharjee, B. Xu, D. A. Frank, G. M. Feldman, and M. K. Cathcart (2006)
J. Immunol. 177, 3771-3781
   Abstract »    Full Text »    PDF »
Congenic Mice Provide in Vivo Evidence for a Genetic Locus that Modulates Serum Insulin-Like Growth Factor-I and Bone Acquisition.
K. M. Delahunty, K. L. Shultz, G. A. Gronowicz, B. Koczon-Jaremko, M. L. Adamo, L. G. Horton, J. Lorenzo, L. R. Donahue, C. Ackert-Bicknell, B. E. Kream, et al. (2006)
Endocrinology 147, 3915-3923
   Abstract »    Full Text »    PDF »
Understanding our drugs and our diseases..
Y. Guo, P. Weller, J. Allard, J. Usuka, M. Masjedizadeh, S.-Y. Wu, B. Fitch, D. Clark, J. D. Clark, S. Shafer, et al. (2006)
Proceedings of the ATS 3, 409-412
   Abstract »    Full Text »    PDF »
PAPPA2, an Enzyme That Cleaves an Insulin-Like Growth-Factor-Binding Protein, Is a Candidate Gene for a Quantitative Trait Locus Affecting Body Size in Mice.
J. K. Christians, A. Hoeflich, and P. D. Keightley (2006)
Genetics 173, 1547-1553
   Abstract »    Full Text »    PDF »
Isolation and Confirmation of a Calcium Excretion Quantitative Trait Locus on Chromosome 1 in Genetic Hypercalciuric Stone-Forming Congenic Rats.
R. R. Hoopes Jr., F. A. Middleton, S. Sen, P. A. Hueber, R. Reid, D. A. Bushinsky, and S. J. Scheinman (2006)
J. Am. Soc. Nephrol. 17, 1292-1304
   Abstract »    Full Text »    PDF »
Sequence Determinants for the Reaction Specificity of Murine (12R)-Lipoxygenase: TARGETED SUBSTRATE MODIFICATION AND SITE-DIRECTED MUTAGENESIS.
S. Meruvu, M. Walther, I. Ivanov, S. Hammarstrom, G. Furstenberger, P. Krieg, P. Reddanna, and H. Kuhn (2005)
J. Biol. Chem. 280, 36633-36641
   Abstract »    Full Text »    PDF »
Return to Ectopia: Stem Cells in the Artery Wall.
L. L. Demer and Y. Tintut (2005)
Arterioscler Thromb Vasc Biol 25, 1307-1308
   Full Text »    PDF »
Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies.
D. Hamerman (2005)
QJM 98, 467-484
   Abstract »    Full Text »    PDF »
A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense.
K. Gronert, N. Maheshwari, N. Khan, I. R. Hassan, M. Dunn, and M. Laniado Schwartzman (2005)
J. Biol. Chem. 280, 15267-15278
   Abstract »    Full Text »    PDF »
Rosiglitazone Causes Bone Loss in Mice by Suppressing Osteoblast Differentiation and Bone Formation.
A. A. Ali, R. S. Weinstein, S. A. Stewart, A. M. Parfitt, S. C. Manolagas, and R. L. Jilka (2005)
Endocrinology 146, 1226-1235
   Abstract »    Full Text »    PDF »
The Roles of Bone Mineral Density, Bone Turnover, and Other Properties in Reducing Fracture Risk During Antiresorptive Therapy.
S. Epstein (2005)
Mayo Clin. Proc. 80, 379-388
   Abstract »    PDF »
Meeting Report from the 26th Annual Meeting of the American Society for Bone and Mineral Research: October 1-5, 2004 in Seattle, Washington, USA.
R. Bouillon, R. F. Klein, Y. Jiang, M. Petit, E. Seeman, P. Ducy, A. A. Reszka, D. Bikle, E. Schipani, G. J. Strewler, et al. (2004)
IBMS BoneKEy 1, 6-50
   Full Text »    PDF »
Thematic review series: The Pathogenesis of Atherosclerosis. Toward a biological network for atherosclerosis.
A. Ghazalpour, S. Doss, X. Yang, J. Aten, E. M. Toomey, A. Van Nas, S. Wang, T. A. Drake, and A. J. Lusis (2004)
J. Lipid Res. 45, 1793-1805
   Abstract »    Full Text »    PDF »
A genome-wide linkage scan for bone mineral density in an extended sample: evidence for linkage on 11q23 and Xq27.
H Shen, Y-Y Zhang, J-R Long, F-H Xu, Y-Z Liu, P Xiao, L-J Zhao, D-H Xiong, Y-J Liu, V Dvornyk, et al. (2004)
J. Med. Genet. 41, 743-751
   Abstract »    Full Text »    PDF »
A Thematic Overview of Some Recent Advances in Skeletal Genetics.
R. D. Blank (2004)
IBMS BoneKEy 1, 4-12
   Full Text »    PDF »
Clues for New Therapeutics in Osteoporosis.
C. N. Serhan (2004)
N. Engl. J. Med. 350, 1902-1903
   Full Text »    PDF »
Skeleton Key.
R. J. Davenport (2004)
Sci. Aging Knowl. Environ. 2004, nf7-7
   Abstract »    Full Text »


To Advertise     Find Products

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