Gene affecting bone mass, osteoporosis risk identified

OHSU, VAMC, Roche scientists use mouse genetics to discover Alox15 gene as potential human therapeutic target

Researchers at Oregon Health & Science University, Portland Veterans Affairs Medical Center and Roche have identified an enzyme affecting skeletal development in mice that may have relevance to human osteoporosis.

The study, titled “Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox 15,” is published in the Friday, Jan. 9 edition of Science, the journal of the American Association for the Advancement of Science.

The gene, Alox15, was isolated from a region of a chromosome known to strongly influence peak bone mineral density (BMD) in mice, according to a study led by the OHSU Bone and Mineral Research Unit and VAMC. Low bone mineral density in early adulthood is considered a major risk factor for osteoporosis in humans.

Robert F. Klein, M.D., OHSU associate professor of medicine and the study’s lead author, said Alox15 was uncovered through analysis of a mouse genetic model of osteoporosis. “Between 60 percent and 80 percent of natural variations in bone density is genetically determined, and understanding this gene’s importance in normal skeletal physiology is a goal of bone and mineral research,” he said. “This is a major step forward.”

Gary Peltz, M.D., Ph.D., head of genetics at Roche Palo Alto and a study co-author, said: “The study demonstrates that mouse genetic discoveries can lead to new opportunities for human therapeutics. It also demonstrates how the rate of genetic discovery was accelerated by coupling genetic analysis of an experimental murine disease model with gene expression analysis.”

Alox15 encodes an enzyme called 12/15-lipoxygenase that converts fatty acids into binding molecules, or ligands, for the peroxisome proliferator-activated receptor-gamma (PPARg). The PPARg receptor is present in many cell types, including pluripotent marrow stem cells that can ultimately develop into either adipocytes (fat cells) or osteoblasts (bone-forming cells).

Stimulation of the PPARg receptor system by increased 12/15-lipoxygenase activity is thought to drive differentiation of the marrow stem cells more towards marrow fat deposition and less towards bone formation, thus contributing to reduced bone density and increased risk for osteoporosis.

“We compared the pattern of gene expression in C57BL/6 and DBA/2 mice, to identify the responsible gene,” Klein said. “Microarray (gene-chip) analysis indicated that Alox15 was the only differentially expressed gene within our region on chromosome 11.” In fact, the rate of the gene’s expression in the low BMD DBA/2 background mice was nearly 20 times that of the congenic high BMD mice.

After showing that over-expression of the 12/15-lipoxygenase enzyme, encoded by the Alox15 gene, kept mice from reaching peak bone mass, the research team treated growing DBA/2 mice with a drug known to inhibit 12/15-lipoxygenase activity. Bone mass and strength during skeletal development improved, demonstrating that drugs can effectively counter the effects of over-activity of the Alox15 gene.

The researchers also found that drugs interfering with the 12/15-lipoxygenase pathway can offset the bone loss accompanying estrogen deficiency. “There are a variety of compounds that interfere with this pathway,” Klein noted.

Osteoporosis is one of the most common bone and mineral disorders in all aging communities. It is characterized by low bone mass, resulting in low bone strength that leads to fractures from relatively minor injuries. An estimated 10 million people suffered from osteoporosis in 2002, and about 80 percent of them are women. An enzyme activated by the gene could be targeted by drugs to prevent this bone-deteriorating disorder, scientists say.

According to the National Osteoporosis Foundation, 55 percent of people ages 50 and older in the United States have either osteoporosis or low bone mass. More than 52 million people are expected to be affected by the diseases by 2010, and that amount is expected to climb to 61 million by 2020.

Eric Orwoll, M.D., professor of medicine at OHSU and a study co-author, said scientists are still years away from finding a cure for osteoporosis. But the Alox15 discovery will heighten understanding of the gene and the receptor pathway it activates, and that could accelerate the tracking of its human counterpart.

Klein and Orwoll pointed out that osteoporosis is caused by a variety of factors, including the interaction of many genes. Lifestyle and environmental factors also play key roles in a person’s risk for the disease. But the Alox15 study, Klein said, “could point to new therapies, a new approach” for treating the disease.

“It points the way toward potent, useful human therapies,” said Orwoll, director of the Bone and Mineral Research Unit. Moreover, the model used to track the Alox15 gene “should be applicable to finding genes for other complex diseases.”

Other study participants at OHSU included: Amy S. Carlos, B.A., research associate; Marie Shea, M.S., assistant professor of orthopaedics and rehabilitation; and John K. Belknap, Ph.D., professor of behavioral neuroscience. Collaborating scientists from Roche, Palo Alto, included: John Allard, Ph.D.; Zafrira Avnur, Ph.D.; Tania Nikolcheva, Ph.D.; David Rotstein, Ph.D.; Ruth V. Waters, B.S.; and Gary Peltz, M.D., Ph.D.