Making bone make more bone

Femur bone cross sections from a wild type mouse and a high bone mass (HBM) mouse. The HBM mouse at right has a much larger bone cross section, with greater spacing between the dyes and evidence of trabecular bone in the marrow space.

Work your bones, get more bone. The link between exercise and bone density has been recognized for a long time. It works like this: As you work out, your muscles pull on your bones, causing strain. Cells embedded in the structure of your bones called osteocytes sense the strain and put out a call to other bone cells, osteoblasts, to start churning out proteins and minerals that make your bones denser and stronger. Which is why a history of load- or weight-bearing exercise can help prevent osteoporosis.

What if we could awaken osteocytes artificially, helping adults and children with brittle bone diseases make more of the bone they need? Scientists may be closing in on a way to do this, using a gene called Lrp5 that plays a key role in passing along the biochemical signals that translate strain into bone.

Ten years ago, geneticist Matthew Warman, who directs the Orthopedic Research Laboratories at Children’s Hospital Boston, found mutations that turn Lrp5 off in children with osteoporosis-pseudoglioma syndrome, which is characterized by brittle bones. He and colleagues at Yale later found mutations that hyperactivate Lrp5 – called high bone mass (HBM) mutations – in people with extra strong bones.

To simulate these effects, a team of academic and industry researchers led by Warman engineered mice to activate these HBM Lrp5 mutations just in osteocytes. In other words, they developed mice with really dense, strong bones.

“These HBM mutations seem to fool the osteocytes, the most mature bone cells, into thinking they hadn’t made enough bone tissue,” he says.

The model is already helping to reveal the roles Lrp5 plays. For example, it showed that Lrp5’s effects are very locally focused. By activating HBM mutations only in osteocytes in the limbs and not in the spine, Warman’s team ended up with mice with really dense bones only in their limbs.

Findings like this could have strong implications for pharmaceutical companies seeking to develop drugs for osteoporosis and other diseases characterized by skeletal fragility. “In fact,” Warman notes, “several companies are pursuing these strategies, and our data provides strong support for their continuing this line of investigation.”

A cross section of bone. Image: BDB/Wikimedia Commons

Warman is particularly interested in figuring out whether tricking osteocytes could help children with a rare genetic disorder called osteogenesis imperfecta. The osteoblasts in these children don’t properly produce type 1 collagen, a protein that acts like a scaffold for bone growth. As a result, their bones remain exceedingly brittle and prone to fracture. Warman believes it may be possible to use Lrp5 to help at least some of these kids grow stronger bones without correcting their underlying collagen defects, a concept he is already starting to pursue.

A bone to pick with serotonin

Warman and his team’s findings stand in stark contrast to earlier research. Three years ago, a research team at Columbia University announced that bone growth and weakness were tied to serotonin (a chemical known better for its role as a neurotransmitter in the brain, but which is also produced in our gut), and that they could prevent osteoporosis in mice with a drug that shut down intestinal serotonin.

This finding took Warman and many in the field of bone physiology and genetics by surprise. And so as part of this study, Warman and his collaborators used the Lrp5 mice to look for relationships between Lrp5 activity and gut serotonin levels, finding none. “We wanted to independently confirm the previous publications which suggested that Lrp5 exerts its effect on bone via intestinal serotonin, but our data do not support this hypothesis,” Warman says.

Warman says that while he finds the notion that gut serotonin affects bone mass is intriguing, he hopes that his team’s results discourage investigators from following it further and instead focus on examining the local role of Lrp5 in bone. “Personally, I think the serotonin connection is incorrect,” he said in a recent New York Times interview. “However, it is perhaps most accurate to state that my lab and several other laboratories have been unable to independently verify the serotonin hypothesis.”