Regulation of bone mass in mice by the lipoxygenase gene Alox15.
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.
Klein
Robert F
RF
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. kleinro@ohsu.edu
Allard
John
J
Avnur
Zafrira
Z
Nikolcheva
Tania
T
Rotstein
David
D
Carlos
Amy S
AS
Shea
Marie
M
Waters
Ruth V
RV
Belknap
John K
JK
Peltz
Gary
G
Orwoll
Eric S
ES
D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics* / Q000378:metabolism*; D015519:Bone Density / Q000187:drug effects / Q000235:genetics*; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005449:Fluorenes / Q000494:pharmacology; D020869:Gene Expression Profiling; D008040:Genetic Linkage; D007668:Kidney / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010012:Osteogenesis; D010024:Osteoporosis / Q000201:enzymology; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
C475064:12-15-lipoxygenase; C106248:6,11-dihydro-5-thia-11-aza-benzo(a)-fluorene; D004791:Enzyme Inhibitors; D005449:Fluorenes; D016859:Lipoxygenase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase