Researchers have used a combination of mouse breeding and genetic technology to identify a gene that strongly influences peak bone mass in mice. The gene, which is present in humans as well as mice, was not previously known to be involved in bone biology, and hence represents a promising new target for development of drugs that could prevent or reverse the bone loss that leads to osteoporosis. Peak bone mass, acquired early in life, is thought to be an important factor in the risk for osteoporosis in humans.
The study, published January 9 in the journal Science, was funded in part by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), one of the Department of Health and Human Services' National Institutes of Health.
Robert F. Klein, M.D., of the Oregon Health and Science University in Portland, and his colleagues studied the offspring of a mating between mouse strains with markedly different peak bone mass, and identified a particular region of one chromosome which influences peak bone mass. Subsequently, their studies of the genes located within this region showed that the Alox15 gene, which produces an enzyme called 12/15-lipoxygenase (12/15-LO), was much more active in the low-bone mass strain than in the high-bone mass strain. Follow-up experiments confirmed the effects of 12/15-LO on bone mass in mice.
In a further phase of the study, the researchers investigated the effect of pharmacological inhibitors of the 12/15-LO enzyme. These drugs had already been developed to inhibit 12/15-LO in other conditions, such as atherosclerosis (clogged arteries), cancer, and asthma, in which this enzyme is also thought to play a role. The use of these drugs resulted in an increase in bone mineral density (BMD) throughout the body in mice that were estrogen-deficient after removal of the ovaries. Reduction in estrogen production with menopause is the major cause of loss of BMD during later life.
According to Dr. Klein, "These results indicate that pharmacological inhibition of 12/15-LO in vivo can improve bone mass and strength during skeletal development as well as offset the bone loss that accompanies estrogen deficiency."
The results of this study merit further animal and human investigation of the role of 12/15-LO in the development of osteoporosis. Osteoporosis is the most common bone and mineral disorder in all aging populations, resulting in fractures from minor trauma. Other factors are also involved in this condition, such as environment, lifestyle and other genetic factors; however, inhibition of 12/15-LO may also be a key to prevention and treatment.
Additional funding for the study was provided by the Northwest Health Foundation and the Veterans Affairs Medical Research Service.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases, the training of basic and clinical scientists to carry out this research, and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at www.niams.nih.gov. Information on osteoporosis is available from the NIH Osteoporosis and Related Bone Diseases~National Resource Center; phone toll-free 800-624-BONE (2663), or visit https://bones.nih.gov/health-info/bone/osteoporosis.
# # #
Klein R, et al. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 2004;303(5655):229-232.