Sci. Aging Knowl. Environ., 14 January 2004
Lipid-processing enzyme weakens bones
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/2/nf7
A protein that oxidizes fat molecules also whittles bones, according to new research. The work shows that rodents with alterations in this enzyme gain a stronger skeleton. The molecule might exert its power by persuading stem cells to become fat cells rather than bone cells.
As we age, bones can thin, a condition known as osteoporosis (see "The Plot Thickens on Thin Bones"). Weakened bones increase the risk of painful or even lethal injuries and limit mobility. Although researchers have pinpointed some triggers for osteoporosis--dwindling sex hormone production, for instance--they need to better understand its mechanism to improve prevention and treatment strategies. Previously, bone researcher Eric Orwoll of Oregon Health & Science University in Portland and colleagues had identified a large region of the mouse genome that is linked to bone density: Changes in that segment appeared to underlie the difference in bone density between two lines of mice.
In the new work, the researchers set their sights on the particular gene that is responsible. To pinpoint it, they replaced the suspect chunk of DNA in the low-bone-density strain with the analogous stretch from the high-bone-density strain and measured bone density using an x-ray densitometer. As predicted, the swap thickened the weak-boned strain's skeleton. Then the team monitored the activity of all the genes in that length of DNA; only one gene's output changed significantly. The Alox15 gene, which produces a protein called 12/15-lipoxygenase that oxidizes lipids, generated one-20th the amount of messenger RNA in brawny-boned rodents as in weak-boned ones. Animals that lack the gene have strong bones, further experiments revealed, suggesting that its activity thins the skeleton.
Those observations suggest that crippling the protein allows rodents to develop dense bones. Additional experiments hint that tying up 12/15-lipoxygenase during adulthood reverses the bone loss of osteoporosis. The team removed the ovaries from female rats--a manipulation that makes bones brittle--and administered a compound that handcuffs 12/15-lipoxygenase. This treatment cut bone loss in half.
How 12/15-lipoxygenase influences bone metabolism isn't clear, but Orwoll notes that oxidized lipids prod a protein called PPAR into action. PPAR is best known for goading bone marrow stem cells to specialize into fat cells, but it also prevents the same stem cells from maturing into bone-building cells. Orwoll proposes that 12/15-lipoxygenase provokes bone loss by prodding PPAR, which diminishes numbers of those bone builders.
"It's an exciting finding," says molecular physiologist Gerard Karsenty of Baylor College of Medicine in Houston, Texas. "They've identified a completely novel pathway [connected to bone loss]." He says he'd like to see a more thorough analysis of bone structure--beyond x-ray measurements--to verify that animals lacking the protein have thicker skeletons. Until now, researchers had focused their attention on the contribution of lipoxygenases and their products to atherosclerosis, says bone biologist Lynda Bonewald of the University of Missouri, Kansas City. This study should convince scientists that these molecules help shape bone as well, she says. If the human gene contributes to bone loss, blocking the fat-tweaking enzyme could offer a new way to bulk up bones.
January 14, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150