Bioengineering

Skeletal strength: Tiny hairs maintain robust bones
The bones on decorative Halloween skeletons or even at the doctor’s office are hard and smooth, but real bones are carpeted with tiny hairs called cilia that stick out of their cells. Didn’t know dem bones had fuzz? Only a few researchers did, and even they didn’t know quite what the cilia were for.  But now a Stanford team may have figured it out. Turns out they seem to play a key role in mechanically sensing motion and then turning on the biochemical processes that maintain healthy bones.

The research was part of an ongoing effort by mechanical engineering and orthopedic surgery Associate Professor Christopher Jacobs to understand at the cellular and molecular level just how putting loads on your skeleton—such as by running— promotes strong bones. This basic investigation could lead to new treatments for tragic diseases such as osteoporosis and lend new insight into how healthy skeletons stay that way. Ultimately, Jacobs hopes he can reveal new cell signals for pharmaceutical researchers to target for drug development.

“Our research is motivated by the fact that physical activity is important to maintaining health in the skeleton,” Jacobs says. “If we can figure out how at the cellular and molecular levels the cells perceive and transduce the information about whether you are loading your skeleton or not, then we could design drugs in the future [that] make it appear to be experiencing healthy loading, even when it may not be.”

In other words, for people who are experiencing bone loss but are unable to exercise, a futuristic drug—maybe 10 years from now—could replace the mechanical stimulation of exercise with a chemical signal. But imagining such a strategy first requires a basic understanding of how cells sense and respond to exercise. That’s where the cilia come in.

Giving bones a haircut
In the Aug. 14 issue of the Proceedings of the National Academy of Sciences, Jacobs’ team reported that the cilia, only 5 millionths of a meter long, bend and sway in fluids that rush past bone cells when people are putting a load on their skeleton (say, by jogging). The researchers showed that this cilia movement is what appears to trigger many of the cells’ biochemical processes for bone maintenance, which involves periodically removing old bone and replacing it with new tissue.

The team, which included researchers from Stanford’s mechanical engineering, bioengineering, biological sciences and genetics departments as well as the Veterans Administration Hospital in Palo Alto, set out to make this discovery by conducting an experiment in the lab. They used two different methods to produce cells without primary cilia: exposing them to a chemical called chloral hydrate and by tinkering with the RNA needed to produce cilia. They left some other bone cells (and their cilia) unaltered as a control group.

With three sets of cells to test they put them in identical environments where fluids would flow past to simulate exercise. They then tracked the cells’ output of various proteins known to have key roles in bone maintenance.

The proteins included osteopontin (OPN), prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2). OPN is a protein that signals that cells are making new bone tissue. PGE2 is necessary for bones to translate motion into the action of bone maintenance. COX2 is needed for producing PGE2. In the lab, Jacobs’ team saw levels of each of these proteins rise substantially when healthy cells were exposed to flow, but no rise or only small rises in the proteins when cells with cilia missing were exposed to flow.

Toward a therapy
The research gives scientists new evidence about what inspires bone cells to produce new bone and remove old bone, but more research is needed to identify how exactly these processes could be stimulated chemically instead of mechanically.

“Presumably there is some kind of chemical released from the cilia when they get disturbed,” Jacobs says. “So researchers would look for a compound that could also cause this signal, even when the cilia have not been moved.”

Such a therapy would be a marked improvement over the current means of treating osteoporosis. The drugs a patient receives today, called bisphospenates, bind to bone tissue and repel the cells that remove old bone tissue. The drugs are good in that they prevent the body from disposing of bone tissue, but they also inhibit the replacement of that tissue with new bone. The ideal therapy, Jacobs says, would allow renovations to proceed just as nature intended.

Translating basic research into therapies is a long process with sometimes daunting odds. But Jacobs is excited about the contributions he can make to medicine as a mechanical engineer.

“A lot of these molecular mechanisms can’t be understood just as chemical reactions,” he says. “This is a great example where a mechanical signal has a lot to do with regulating a molecular process.”

October 2007