A common misconception is that osteoporosis is a 'disease of old age'. In fact, the reduction in bone density that causes osteoporosis begins as early as 25, but because the loss is gradual and initially asymptomatic, this 'silent disease' often goes unnoticed until it reaches an advanced stage, when bones break or fracture. Lifestyle factors, such as poor diet, can contribute to the development of osteoporosis, but genetics also has an important role to play, and in a recent issue of Science, Robert Klein and colleagues describe how experiments in mice have uncovered a gene that could be relevant to human osteoporosis.

To identify genes that might regulate bone density, the researchers looked at a region of chromosome 11 that has been linked to peak bone mineral density (BMD) levels in mice. First, they bred two strains of mice (DBA/2 (D2) and C57BL/6 (B6)) that differ at the region of interest on chromosome 11, and found that B6 mice had higher peak BMD and increased bone strength than their D2 littermates. Microarray analysis was then used to compare gene expression in D2 and B6 mice, and the researchers found that Alox15 was the only differentially expressed gene within the region of interest. In fact, Alox15 expression was nearly 20 times higher in D2 mice compared with B6 mice.

Alox15 encodes the enzyme 12/15-lipoxygenase (12/15-LO), which converts fatty acids into ligands for the peroxisome proliferator-activated receptor-γ (PPAR-γ). This receptor is found on the surface of many cells, including pluripotent stem cells in the bone marrow that give rise to many cell types, such as adipocytes (fat cells) and osteoblasts (bone-forming cells). As activation of PPAR-γ had previously been shown to drive the differentiation of marrow stem cells towards fat deposition at the expense of bone formation, Klein and colleagues suggested that overexpression of 12/15-LO might limit BMD by suppressing bone formation through activation of PPAR-γ.

To confirm their hypothesis in vivo, the authors showed that bone density and strength were increased in B6 12/15-LO knockout mice compared with age-matched B6 controls. In addition, knocking out 12/15-LO rescued D2 mice from the low-bone-mass phenotype associated with the D2 strain.

To see if inhibition of 12/15-LO could rescue the low bone density associated with over-activity of the Alox15 gene, the authors treated growing B6 mice overexpressing Alox15 with the specific 12/15-LO inhibitor PD146176, which improved both bone density and strength compared with untreated controls. They then used a rat model of oestrogen deficiency to show that 12/15-LO inhibitors could not only improve bone mass during development, but also offset the bone loss that is associated with oestrogen deficiency.

The authors suggest that these findings in mice could have relevance to human osteoporosis, especially as a region of human chromosome 17 that contains the genes encoding 12-LO and 15-LO has already been linked to low bone density. And if a role for the 12/15-LO pathway in regulating human bone mass is confirmed, inhibitors of this enzyme that are already under development for other indications, including atherosclerosis, could provide a good starting point for preventing the silent progression of osteoporosis in humans.